Clinical Trials /

Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer

NCT03801369

Description:

This phase II study assesses the efficacy of the combination of olaparib and durvalumab in the treatment of patients with metastatic triple negative breast cancer (TNBC). Olabparib may stop growth of tumors cells by inhibiting some of the enzymes (ADP ribose polymerase (PARP)) needed for cell growth. Durvalumab, a monoclonal antibody, inhibits the growth and spread of tumors by stimulating the patient's antitumor immune response. Giving olaparib and durvalumab together may provide an effective method to treat patients with metastatic triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer
  • Official Title: A Phase II, Open Label, Study of Olaparib and Durvalumab (MEDI4736) in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: STUDY00018504
  • NCT ID: NCT03801369

Conditions

  • Metastatic Triple Negative Breast Cancer
  • Breast Cancer
  • ER-Negative PR-Negative HER2-Negative Breast Cancer
  • ER-Negative PR-Negative HER2-Negative Breast Neoplasms
  • Triple-Negative Breast Cancer
  • Triple Negative Breast Cancer
  • Triple-Negative Breast Neoplasm

Interventions

DrugSynonymsArms
OlaparibTreatment (Olaparib and Durvalumab)
DurvalumibMEDI4736Treatment (Olaparib and Durvalumab)

Purpose

This phase II study assesses the efficacy of the combination of olaparib and durvalumab in the treatment of patients with metastatic triple negative breast cancer (TNBC). Olabparib may stop growth of tumors cells by inhibiting some of the enzymes (ADP ribose polymerase (PARP)) needed for cell growth. Durvalumab, a monoclonal antibody, inhibits the growth and spread of tumors by stimulating the patient's antitumor immune response. Giving olaparib and durvalumab together may provide an effective method to treat patients with metastatic triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess overall response to treatment

      SECONDARY OBJECTIVES:

      I. Assess participant benefit from treatment

      II. Determine the time to disease progression following response to study therapy

      III. Determine time to first disease progression or death of participants enrolled on the
      study

      IV. Determine survival of participants enrolled on the study

      V. Assess safety and tolerability of the proposed therapy

      EXPLORATORY OBJECTIVES:

      I. Examine response rates depending on tumor characteristics

      II. Identify predictive biomarkers of sensitivity to therapy

      III. Identify emerging mechanism of resistance to therapy

      IV. Determine changes in tumor cells induced by PARP inhibitors

      OUTLINE: This is an open-label, single-arm phase II study of olaparib and durvalumab.

      Participants with biopsy proven TNBC will undergo a pre-treatment biopsy, after which they
      will receive a 4 week, single cycle, induction treatment of olaparib (oral, twice a day). At
      the 4 week mark, participants will then undergo a repeat on-treatment biopsy, following which
      durvalumab will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib.
      Treatment courses repeat every 28 days for 12 cycles.

      At the completion of all on-study procedures, participants will be considered off-treatment
      and will be followed every 6 months for disease and survival outcomes up to 1 year.
      Participants will be asked to submit an optional tumor biopsy in the event of disease
      progression.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (Olaparib and Durvalumab)ExperimentalParticipants receive a 4 week, single cycle, induction treatment of olaparib (oral, twice a day). At the 4 week mark, participants will then undergo a repeat on-treatment biopsy, following which durvalumib will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib. Treatment courses repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Durvalumib

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Participants are >= 18 years old at time of informed consent.

          -  Metastatic TNBC, as defined by:

               1. ER and PR negative as defined as ER < 10% and PR < 10% by immunohistochemistry
                  according to American Society of Clinical Oncology (ASCO)/College of American
                  Pathologists (CAP) guidelines for hormone receptor testing

               2. HER2 non-amplified per ASCO/CAP guidelines, defined as:

                    1. IHC score 0/1+

                    2. IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
                       CEP17 < 2.0, and if reported, average HER2 gene copy number <4
                       signals/cells; or

                    3. ISH non-amplified with a ratio of HER2 to CEP17 <2.0, and if reported,
                       average HER2 gene copy number < 4 signals/cells

          -  Participants must have at least one measurable site of disease as defined by RECIST
             v1.1 that is amendable to biopsy.

          -  Prior therapies for metastatic breast cancer

               1. Frontline patients who have not received prior systemic therapy for metastatic
                  breast cancer are eligible.

               2. Patients who have received <= 2 prior chemotherapy regimens for metastatic breast
                  cancer are eligible.

          -  Participants must have fully recovered from the acute toxic effects of all prior
             treatment to grade 1 or less, except alopecia and <= Grade 2 neuropathy which are
             allowed

          -  Participants must have a life expectancy >=16 weeks.

          -  Participant must have Eastern Cooperative Oncology Group (ECOG) performance status <=1

          -  Participant must consent to undergo a pre-treatment screening biopsy for enrollment
             and subsequent biomarker analyses.

          -  Participants must consent to undergo one mandatory on-study tumor biopsy following a 4
             week, single cycle induction treatment of olaparib. A second on-study biopsy at time
             of disease progression is optional, but not mandatory.

          -  Participants must not have had prior immunotherapy with anti-PD-L1, including
             durvalumab anti-PD-1, anti-CTLA4 or similar drugs.

          -  Participants must not have received previous treatment with PARP inhibitors, including
             olaparib.

          -  Participants must have normal organ and bone marrow function measured within 28 days
             prior to administration of study treatment as defined below:

               1. Haemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days

               2. Absolute neutrophil count (ANC) >= 1.5 x 109/L

               3. Platelet count >= 100 x 109/L

               4. Total bilirubin <= 1.5 x institutional upper limit of normal (ULN)

               5. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
                  / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) <=
                  2.5 x institutional upper limit of normal unless liver metastases are present in
                  which case they must be <= 5x ULN

               6. Participants must have creatinine clearance estimated of >= 51 mL/min using the
                  Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine
                  clearance = (140-age [years]) x weight (kg) (x F) serum creatinine (mg/dL) x 72;
                  where F=0.85 for females and F=1 for males.

          -  Female participants of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study medication.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required.

          -  Female participants of childbearing potential agree to use adequate methods of
             contraception starting with the first dose of study therapy through 60 days after the
             last dose of study therapy. Participants of childbearing potential are those who are
             not proven postmenopausal. Postmenopausal is defined as:

               1. Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               2. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
                  post menopausal range for women under 50

               3. Radiation-induced oophorectomy with last menses > 1 year ago

               4. Chemotherapy-induced menopause with > 1 year interval since last menses

               5. Surgical sterilisation (bilateral oophorectomy or hysterectomy)

          -  Male participants must agree to use an adequate method of contraception starting with
             the first dose of study therapy through 60 days after the last dose of study therapy.

          -  Participants must not have received live vaccines within 30 days prior to the first
             dose of immunotherapy. Examples of live vaccines include, but are not limited to, the
             following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG,
             and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally
             killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
             Flu-Mist®) are live attenuated vaccines, and are not allowed. Patients, if enrolled,
             should not receive live vaccine whilst receiving immunotherapy and up to 30 days after
             the last dose of immunotherapy

        Exclusion Criteria:

          -  Currently participating and receiving study therapy or has participated in a study of
             an investigational agent and received study therapy or used an investigation device
             within 4 weeks of first dose of treatment.

             a. Individuals in the follow-up phase of a prior investigational study may participate
             as long as it has been 4 weeks since last dose of the previous investigational agent
             of device.

          -  Participants with germline BRCA mutated TNBC will be excluded

          -  Other malignancy unless curatively treated with no evidence of disease for >= 5 years
             except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
             of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial
             carcinoma. Participants with a history of localized triple negative breast cancer may
             be eligible, provided they completed their adjuvant chemotherapy more than three years
             prior to registration, and that the participant remains free of recurrent or
             metastatic disease

          -  Participants with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of MDS/AML.

          -  Participant received prior chemotherapy or any other targeted therapies within the
             past 28, or radiation (except for palliative reasons) within the past 3 weeks, prior
             to going on-study.

          -  Participants with known active central nervous system (CNS) metastases and/or
             carcinomatous meningitis.

          -  Participants with previously treated brain metastases may participate provided they
             are stable [without evidence of progression by imaging (confirmed by CT scan if CT
             used at prior imaging, or confirmed by MRI if MRI was used at prior imaging) for at
             least four weeks prior to the first dose of trial treatment and any neurologic
             symptoms have returned to baseline], have no evidence of new or enlarging brain
             metastases, and are not using steroids for at least 7 days prior to trial treatment.
             This exception does not include carcinomatous meningitis which is excluded regardless
             of clinical stability.

          -  Participants unable to swallow orally administered medication and participants with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Participants with visceral crisis defined as severe organ dysfunction as assessed by
             signs and symptoms, laboratory studies, and rapid progression of disease.

          -  Active infection requiring systemic antibiotic therapy. Participants requiring
             systemic antibiotics for infection must have completed therapy before treatment is
             initiated.

          -  Participants considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, 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
             illness/social situation that prohibits obtaining informed consent.

          -  Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
             judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
             arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
             disturbances, etc.), or participants with congenital long QT syndrome

          -  Participants with a history of hypersensitivity reactions to study agent or their
             excipients.

          -  Participant is pregnant or breastfeeding, or expecting to conceive or father children
             within the projected duration of the trial, starting with the screening visit through
             120 days after the last dose of trial treatment.

          -  Involvement in the planning and/or conduct of the study

          -  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.

        DRUG-SPECIFIC EXCLUSION CRITERIA: Durvalumab

          -  Participant has evidence of interstitial lung disease or active non-infectious
             pneumonitis.

          -  Major surgery within 2 weeks of starting study treatment and participants must have
             recovered from any effects of any major surgery Note: Local surgery of isolated
             lesions for palliative intent is acceptable per investigator discretion.

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

          -  History of active primary immunodeficiency

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid. The following are exceptions to this
             criterion:

               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
             criterion:

               1. Participants with vitiligo or alopecia

               2. Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               3. Any chronic skin condition that does not require systemic therapy

               4. Participants without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               5. Participants with celiac disease controlled by diet alone

          -  History of allogenic bone marrow transplant or double umbilical cord blood
             transplantation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to 6 months post treatment
Safety Issue:
Description:Using the efficacy analysis set, the estimate of ORR will be measured and reported with 95% exact confidence interval. Participants who achieve a complete response (CR) or a partial response (Pr) on the current protocol will be qualified as achieving a response, and will count towards the ORR measurement.

Secondary Outcome Measures

Measure:Incidence of grade 3+ acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0
Time Frame:Up to 3 months post treatment
Safety Issue:
Description:Incidence will be determined for participants with TNBC that received at least one dose of olaparib and/or durvalumab. The 95% confidence interval will be reported with the point estimate of toxicity rate
Measure:Clinical benefit rate (CBR) for olaparib in combination with durvalumab
Time Frame:Up to 6 months post treatment
Safety Issue:
Description:An estimate of CBR will be measured and reported with 95% exact confidence interval. Participants who achieve a CR, Pr, or stable disease (SD) for at least 6 months on the current protocol will be qualified as deriving benefit from therapy, and will count towards the CBR measurement.
Measure:Progression-free survival (PFS) for olaparib in combination with durvalumab
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:PFS is defined as the time from first treatment with olaparib (i.e., cycle 1 day 1) to the first of either recurrence or relapse (anywhere in the body), or death at time of last follow-up at 12-months. The estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available
Measure:Overall survival (OS) olaparib in combination with durvalumab
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:OS is defined as the time from first treatment with olaparib (i.e., Day 1) to the date of death or last follow-up at 12 months. The estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available.
Measure:Duration of response (DOR) for olaparib in combination with durvalumab
Time Frame:Up to 6 months post treatment
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR or Pr (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented taking as reference for progressive disease the smallest measurements recorded since the treatment started. The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. If a participant dies, irrespective of cause, without documentation of recurrent or progressive disease beforehand, then the date of death will be used to denote the response end date.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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