Clinical Trials /

Window of Opportunity Trial of Neoadjuvant Olaparib and Durvalumab for Triple Negative or Low ER+ Breast Cancer

NCT03594396

Description:

Window of Opportunity Trial of Olaparib and Durvalumab (MEDI4736) before Standard Neoadjuvant Chemotherapy for Stage II/III Triple Negative or Low ER+ Breast Cancer

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Window of Opportunity Trial of Neoadjuvant Olaparib and Durvalumab for Triple Negative or Low ER+ Breast Cancer
  • Official Title: Window of Opportunity Trial of Olaparib and Durvalumab (MEDI4736) Before Standard Neoadjuvant Chemotherapy for Stage II/III Triple Negative or Low ER+ Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: S1709-101-888
  • NCT ID: NCT03594396

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
OlaparibLynparzaMEDIOLA
DurvalumabIMFINZI, MEDI4736MEDIOLA

Purpose

Window of Opportunity Trial of Olaparib and Durvalumab (MEDI4736) before Standard Neoadjuvant Chemotherapy for Stage II/III Triple Negative or Low ER+ Breast Cancer

Detailed Description

      This is a non-randomized, prospective, open label, window pilot study to evaluate the change
      of tumor biology after olaparib and durvalumab treatment by serial biopsy of breast cancer.
    

Trial Arms

NameTypeDescriptionInterventions
MEDIOLAExperimentalPrior to the start of study medication, tumor tissue and blood will be collected as baseline. Olaparib 300mg bid will be started after the collection of tumor and blood. Olaparib will be given on days 1-28 days without rest. Tumor tissue and blood will be collected on day 14 before administration of durvalumab, to see the change in biomarkers after 2 weeks of olaparib treatment. After the acquisition of tumor and blood, durvalumab will be given in a fixed one dose of 1.5 gram on day 15. On day 29, there will be a third acquisition of tumor and blood, to see the change in biomarkers after combination treatment of olaparib and durvalumab. Tumor response will also be evaluated according to RECIST criteria version 1.1 based on CT.
  • Olaparib
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          -  Nineteen years of age or older on the day of signing informed consent.

          -  Willing and able to provide written informed consent for voluntary participation in
             the trial.

          -  Has previously untreated, clinical stage II/III triple negative breast cancer (TNBC)
             or low estrogen receptor (ER) tumor where ER is expressed in ≤10% tumor cells) .

          -  Willing to provide biopsies from the primary tumor or lymph nodes at screening to the
             central laboratory and agrees to have a core needle biopsy or incisional or excisional
             tumor biopsy after 14 days and 28 days of olaparib treatment (before and after
             durvalumab treatment) if tumor biopsy is feasible as judged by the investigator.

          -  Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by
             history: ≥60 years old and no menses for >1 year without an alternative medical cause;
             OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
             bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
             and agree to use contraception if they or their partner are of reproductive potential.

          -  Has adequate organ function.

               -  Hemoglobin ≥ 10.0 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)

               -  Platelet count ≥ 100 x 109/L (>100,000 per mm3)

               -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless due to Gilbert's syndrome

               -  INR/PT/APTT each ≤ 1.5 x ULN

               -  TSH within normal limits

               -  Serum creatinine < 1.5 x ULN or serum creatinine CL > 51 mL/min by the
                  Cockcroft-Gault formula (Cockroft and Gault 1976) or by 24-hour urine collection
                  for determination of creatinine clearance

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

        Exclusion Criteria:

          -  Underweighted populations - ≤30kg

          -  Has evidence of metastatic breast cancer, inflammatory breast cancer, or concurrent
             bilateral invasive breast cancer where ER is expressed in >10% tumor cells.

        (Note) Patients with bilateral invasive breast cancers can be enrolled if both tumors are
        TNBCs, including low estrogen receptor (ER) tumor where ER is expressed in ≤10% tumor
        cells.

        • Has another malignancy within the last 3 years. Exceptions include basal cell carcinoma
        of the skin, squamous cell carcinoma of the skin, and thyroid cancer that has undergone
        potentially curative surgery, or in situ cervical cancer.

        (Note) These patients should be consulted to the principal investigator for a case-by-case
        decision before enrollment.

          -  Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy
             that targets immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell
             receptors within the past 12 months.

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab

          -  Is currently participating and receiving study therapy, or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of study drug.

          -  Has received a live vaccine within 30 days of the first dose of durvalumab. Note:
             Patients, if enrolled, should not receive live vaccine up to 30 days after the last
             dose of IP.

          -  Has an active autoimmune disease or inflammatory disorders (including inflammatory
             bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of
             diverticulosis], celiac disease, irritable bowel disease, or other serious
             gastrointestinal chronic conditions associated with diarrhea, systemic lupus
             erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
             polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.])
             that has required systemic treatment in past 2 years. The followings are exceptions to
             this criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement or psoriasis not requiring systemic treatment.

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 3 years may be included but only
                  after consultation with the principal investigator.

               -  Patients with celiac disease controlled by diet alone may be included but only
                  after consultation with the principal investigator.

          -  Has a diagnosis of immunodeficiency

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,
                  intra-articular injection)

               -  Systemic corticosteroid at physiologic dose not to exceed 10 mg/day of prednisone
                  or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication)

          -  Has a known history of Human Immunodeficiency Virus (HIV).

          -  Active infection, including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus
             (HIV, positive HIV 1 or 2 antibodies). Active hepatitis B virus (HBV) infection is
             defined by a positive HBV surface antigen (HBsAg) and positive titer for HBV
             DNA.result. Patients with a past or resolved HBV infection (defined as the presence of
             hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA]
             negative) are eligible. Patients positive for hepatitis C virus (HCV) antibody are
             eligible only if polymerase chain reaction is negative for HCV ribonucleic acid
             (RNA)..

          -  Has evidence of active, non-infectious pneumonitis.

          -  Has history of pneumonitis requiring treatment with steroids or history of
             interstitial lung disease.

          -  Has an active infection requiring systemic therapy.

          -  Has significant cardiovascular disease, such as: History of myocardial infarction,
             acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the
             last 6 months; Congestive heart failure (CHF) New York Heart Association (NYHA) Class
             II-IV or history of CHF NYHA class III or IV

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the study.

          -  Is pregnant or breastfeeding, or expecting to conceive children within the projected
             duration of the study, starting with the screening visit through 120 days after the
             last dose of study drug.

          -  Has a known hypersensitivity to the components of the study drug or its analogs.

          -  Concurrent use of any medications or substances that are strong inhibitors of
             cytochrome P450 (CYP) 3A (CYP3A), such as ketoconazole, itraconazole, ritonavir,
             indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir, or strong
             inducers of CYP3A4. Dihydropyridine calcium-channel blockers are permitted for
             management of hypertension.

          -  Previous allogenic bone marrow transplant or (single) umbilical cord blood
             transplantation

          -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, as long as not received within
             28 days of start of treatment.

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Frediricia's Correction within 14 days of treatment

          -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

          -  Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
             consultation with the Study Physician.

          -  Subjects with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with durvalumab may be included only after consultation with the Study
             Physician

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
             acceptable.

          -  History of leptomeningeal carcinomatosis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The changes of tumor biology
Time Frame:28 days
Safety Issue:
Description:The changes of tumor biology detected by serial biopsy of breast cancer before and after olaparib and durvalumab (exploratory serial biopsy study)

Secondary Outcome Measures

Measure:pathological complete response
Time Frame:7 months
Safety Issue:
Description:Number of participants with a pathological complete response (ypT0/Tis, ypN0).
Measure:Response rate
Time Frame:7 months
Safety Issue:
Description:Response rate by RECIST v.1.1
Measure:Treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:7 months
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measure:Adverse events of special interest and immune-mediated adverse events
Time Frame:7 months
Safety Issue:
Description:Adverse events of special interest and immune-mediated adverse events

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seoul National University Hospital

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