Clinical Trials /

Durvalumab, With Olaparib and Fulvestrant in Advanced ER+, HER2- Breast Cancer Patients.

NCT04053322

Description:

This study evaluates the efficacy of the combination of olaparib, durvalumab, and fulvestrant for the treatment of patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with BRCA gene alterations or alterations of genes involved in homologous recombination repair (HRR) or microsatellite instability (MSI) status.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/II Trial Assessing Durvalumab, With Olaparib and Fulvestrant in Advanced ER+, HER2- Breast Cancer Patients.
  • Official Title: An International Multicenter Phase II Trial of Durvalumab (MEDI4736) Plus OLAparib Plus Fulvestrant in Metastatic or Locally Advanced ER-positive, HER2-negative Breast Cancer Patients Selected Using Criteria That Predict Sensitivity to Olaparib

Clinical Trial IDs

  • ORG STUDY ID: UC-0140/1812
  • NCT ID: NCT04053322

Conditions

  • ER-positive and HER2-negative Metastatic or Locally Advanced Breast Cancer
  • a Germline or Somatic BRCA Mutation, or a Deleterious Alteration of Other Genes Involved in Homologous Recombination Repair (HRR) or in MSI Status

Interventions

DrugSynonymsArms
DurvalumabStudy Arm
OlaparibStudy Arm
FulvestrantStudy Arm

Purpose

This study evaluates the efficacy of the combination of olaparib, durvalumab, and fulvestrant for the treatment of patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with BRCA gene alterations or alterations of genes involved in HRR or MSI status.

Trial Arms

NameTypeDescriptionInterventions
Study ArmExperimental
  • Durvalumab
  • Olaparib
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

        DIAGNOSIS AND INCLUSION CRITERIA:

          1. Histologically confirmed ER-positive (≥10%), HER2-negative (0, 1+, 2+, and no HER2
             gene amplification by ISH), metastatic or locally advanced breast cancer that is not
             amenable to resection or radiation with curative intent.

          2. Patients aged ≥18 years old (post-menopausal or pre/per-menopausal women and men).

          3. Documented personal germline alteration in BRCA1 or BRCA2 that is predicted to be
             deleterious. Testing may be performed at any time prior to inclusion.

             OR Deleterious germline or somatic alterations implicated in the HRR pathway (ATM,
             BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN,
             PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other
             actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central
             tumor next generation DNA sequencing performed at screening visit.

             A tumor biopsy sample must be available: if obtaining an adequate metastatic tumor
             biopsy is impossible (including bone metastasis), analyses will be done on a biopsy
             from the primary breast tumor.

          4. Patients with a life expectancy ≥16 weeks.

          5. ECOG performance status 0-1.

          6. At least one evaluable lesion, either measurable or non-measurable that can be
             accurately assessed at baseline by CT-scan or MRI by RECIST v1.1.

          7. Patients could have received 1 line of endocrine therapy (including CDK4/6 inhibitor,
             but excluding fulvestrant or mTOR inhibitor) and/or 1 line of chemotherapy in the
             metastatic setting.

          8. Within 28 days prior to administration of study treatment, patients must have adequate
             organ and bone marrow functions:

               -  Hemoglobin ≥10 g/dL with no blood transfusion in the past 28 days.

               -  Absolute neutrophil count (ANC) ≥1.5 x 109/L.

               -  Platelet count ≥100 x 109/L.

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

               -  AST/ALT ≤2.5 x institutional ULN unless liver metastases are present in which
                  case AST/ALT levels must be ≤5 x ULN.

               -  Estimated creatinine clearance ≥ 51 mL/min according to the Cockcroft-Gault
                  equation or based on a 24-hour urine test.

          9. Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of study treatment
             and confirmed prior to treatment on day 1.

         10. Woman of childbearing potential patients must agree to use adequate contraception for
             the duration of trial participation and up to 3 months after the last dose of
             olaparib.

             Male patients must use a condom during treatment and for 3 months after the last dose
             of olaparib when having sexual intercourse with a pregnant woman or with a woman of
             childbearing potential. Female partners of male patients should also use a highly
             effective form of contraception.

         11. Patients having provided written informed consent prior to any study-related
             procedures.

         12. Patient is willing and able to comply with the protocol for the duration of the study.

         13. Patients must have national social insurance coverage (applicable only in France).

        Exclusion Criteria:

        NON INCLUSION CRITERIA:

          1. Patients without olaparib targetable genomic anomaly identified during the screening
             phase.

          2. Gene variants (class 1, 2, and 3) of unknown significant prognostic for olaparib
             sensitivity.

          3. Patients with history of other malignancy except non-melanoma skin cancer, in-situ
             cancer of the cervix, or solid tumors including lymphomas (without bone marrow
             involvement) curatively treated and with no evidence of disease for ≥5 years prior to
             study entry.

          4. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of myelodysplastic syndrome/acute myeloid leukemia.

          5. Patients with symptomatic uncontrolled brain metastases. In addition, treatment of the
             central nervous system disease must have finished (whole brain radiation,
             radiosurgery) at least 2 weeks before Cycle 1 Day 1. Patients must not require >10 mg
             of prednisone per day or an equivalent dose of other corticosteroids.

          6. Prior treatment with a PARP inhibitor (including olaparib) and/or PD-1 or PD-L1
             inhibitor (including durvalumab).

          7. Patients having received anticancer chemotherapy or any other investigational therapy
             within 3 weeks prior of the study. Endocrine therapy must have been discontinued 7 or
             more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 or
             more days before Cycle 1 Day 1. Biphosphonates and denosumab are allowed.

          8. Major surgery within 2 weeks prior to registration. Patients must have recovered from
             earlier major surgery before registration.

          9. Persistent toxicities (NCI-CTCAE grade ≥2) caused by previous cancer therapy,
             excluding alopecia and peripheral neuropathy (grade ≤2).

         10. Patients with known history of bleeding diathesis or hemorrhage.

         11. 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 (known positive HBV surface antigen [HBsAg]
             result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2
             antibodies). Patients with a past or resolved HBV infection (defined as the presence
             of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
             positive for HCV antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

         12. Patients considered at poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection,
             symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
             pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, and active
             bleeding diatheses. Recent (within 3 months) myocardial infarction, uncontrolled major
             seizure disorder, unstable spinal cord compression, superior vena cava syndrome,
             extensive interstitial bilateral lung disease on High Resolution Computed Tomography
             (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent.

         13. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
             judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic
             arrhythmia, congestive heart failure, QTcF prolongation >470 ms, electrolyte
             disturbances, etc.), or patients with congenital long QT syndrome.

         14. Current or prior use of immunosuppressive medication within 28 days before the first
             dose of durvalumab, with the exceptions of intranasal or inhaled corticosteroids or
             systemic corticosteroids at physiological doses, not exceeding 10 mg/day of
             prednisone, or an equivalent corticosteroid.

         15. Active or prior documented autoimmune disease within the past 2 years except for
             patients with vitiligo or psoriasis without systemic treatment during the past 2
             years.

         16. Active or prior documented inflammatory bowel disease (Crohn's disease, ulcerative
             colitis).

         17. History of allogeneic organ transplant, including previous allogenic bone marrow
             transplant or double umbilical cord blood transplantation.

         18. Received live attenuated vaccination within 30 days prior to study entry.

         19. Patients unable to swallow orally administered medication, patients with
             gastrointestinal disorders likely to interfere with the absorption of olaparib, and
             patients with long-term oral anticoagulant therapy (excluding Warfarin).

         20. Pregnant or breast feeding women.

         21. Known hypersensitivity to durvalumab, olaparib, and/or fulvestrant or any of the
             excipients of these products.

         22. Concomitant use of a known :

               -  Strong or moderate CYP3A inhibitors. The required washout period prior to
                  starting olaparib is 2 weeks.

               -  Strong or moderate CYP3A inducers. The required washout period prior to starting
                  olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other
                  agents.

             Warning: For men and pre/per-menopausal women who will receive goserelin (Zoladex®) in
             combination with study drugs, the use of concomitant drugs which can prolong the QT
             interval or induce Torsades de pointes should be evaluated with caution.

         23. Whole blood transfusions in the 120 days prior to study enrolment (packed red blood
             cells and platelet transfusions are acceptable, if outside of 28 days prior to
             treatment).

         24. Persons deprived of their liberty or under protective custody or guardianship.

         25. Patients enrolled in another therapeutic study within 30 days prior inclusion.

         26. Involvement in the planning and/or conduct of the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival rate (PFSR)
Time Frame:24 weeks
Safety Issue:
Description:The progression-free survival rate at 24 weeks defined as the percentage of patients alive without disease progression at 24 weeks after inclusion. PFSR will be evaluated by local investigator using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). The death of a patient for any cause within 24 weeks will be considered as failure

Secondary Outcome Measures

Measure:The incidence of adverse events (Safety)
Time Frame:6 years
Safety Issue:
Description:Adverse events will be graded using NCI-CTCAE v5.0
Measure:Overall Survival
Time Frame:6 years
Safety Issue:
Description:OS is defined as the interval between the date of inclusion and the date of death from any cause. A patient alive will be censored at the last date of follow-up
Measure:Objective response rate (ORR)
Time Frame:3 years
Safety Issue:
Description:The ORR defined as the percent of patients with a complete response (CR) or a partial response (PR).
Measure:Duration of response (DoR).
Time Frame:3 years
Safety Issue:
Description:The DoR defined as the duration between the time measurement criteria are first met for CR or PR until the first date that recurrent disease is objectively documented
Measure:Progression-free survival
Time Frame:6 years
Safety Issue:
Description:PFS defined as the interval between the date of inclusion and the date of progression or death. A patient alive and without progression will be censored at the last date of follow-up.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNICANCER

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