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Olaparib and Durvalumab in Treating Patients With Metastatic Triple Negative Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03801369
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : June 29, 2020
Sponsor:
Collaborators:
AstraZeneca
National Cancer Institute (NCI)
Oregon Health and Science University
Information provided by (Responsible Party):
Zahi Mitri, MD, MS, OHSU Knight Cancer Institute

Brief Summary:
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). Olaparib 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.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Triple-Negative Breast Carcinoma Prognostic Stage IV Breast Cancer AJCC v8 Biological: Durvalumab Drug: Olaparib Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

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.

Patients with biopsy proven TNBC will undergo a pre-treatment biopsy, after which they will receive a 28 days induction treatment of olaparib (oral, twice a day). At the 2 week mark, patients will then undergo a repeat on-treatment biopsy. Beginning cycle 2, durvalumab will be administered (intravenously [IV] over 1 hr) every 4 weeks, in addition to olaparib. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, may continue on therapy beyond the planned 13 cycles.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open Label, Study of Olaparib and Durvalumab (MEDI4736) in Patients With Metastatic Triple Negative Breast Cancer
Actual Study Start Date : December 12, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (Olaparib and Durvalumab)
Patients with biopsy proven TNBC will undergo a pre-treatment biopsy, after which they will receive a 28 days induction treatment of olaparib (oral, twice a day). At the 2 week mark, patients will then undergo a repeat on-treatment biopsy. Beginning cycle 2, durvalumab will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, may continue on therapy beyond the planned 13 cycles.
Biological: Durvalumab
Given IV (infusion)
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Drug: Olaparib
Given PO (orally)
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 6 months post treatment ]
    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 :
  1. Incidence of grade 3+ acute toxicity [ Time Frame: Up to 3 months post treatment ]
    Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Incidence will be determined for participants with triple negative breast cancer (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.

  2. Clinical benefit rate (CBR) for olaparib in combination with durvalumab [ Time Frame: Up to 6 months post treatment ]
    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.

  3. Progression-free survival (PFS) for olaparib in combination with durvalumab [ Time Frame: Up to 1 year post treatment ]
    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.

  4. Overall survival (OS) olaparib in combination with durvalumab [ Time Frame: Up to 1 year post treatment ]
    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.

  5. Duration of response (DOR) for olaparib in combination with durvalumab [ Time Frame: Up to 6 months post treatment ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to understand and the willingness to sign a written informed consent document
  • Metastatic triple negative breast cancer (TNBC), as defined by:

    • Estrogen receptor (ER) and progesterone receptor (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
    • HER2 non-amplified per ASCO/CAP guidelines, defined as:

      • IHC score 0/1+
      • 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
      • 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 Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 that is amenable to biopsy
  • Prior therapies for metastatic breast cancer

    • Frontline patients who have not received prior systemic therapy for metastatic breast cancer are eligible
    • 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 2 week 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 in the metastatic setting
  • Participants may have received prior immunotherapy in the adjuvant setting, provided

    • No documented disease progression on immunotherapy
    • Treatment with immunotherapy was > 1 year from enrollment on study
  • Participants must not have received previous treatment with PARP inhibitors, including olaparib
  • Hemoglobin >= 10.0 g/dL (measured within 28 days prior to administration of study treatment) with no blood transfusion in the past 28 days
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior to administration of study treatment)
  • Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)
  • 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 =< 5 x ULN (measured within 28 days prior to administration of study treatment)
  • Participants must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (measured within 28 days prior to administration of study treatment)
  • 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:

    • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    • Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
    • Radiation-induced oophorectomy with last menses > 1 year ago
    • Chemotherapy-induced menopause with > 1 year interval since last menses
    • Surgical sterilization (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, Bacillus Calmette-Guerin (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.

    • 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 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
  • Participant received prior chemotherapy within the past 28 days, prior targeted therapies within the past 14 days, or radiation (except for palliative reasons) within the past 3 weeks, prior to first day of treatment"
  • 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 computed tomography (CT) scan if CT used at prior imaging, or confirmed by magnetic resonance imaging (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 electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fridericia's correction formula (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
  • DURVALUMAB DRUG-SPECIFIC EXCLUSION CRITERIA:
  • 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 tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [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 ribonucleic acid (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:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • 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:

    • Participants with vitiligo or alopecia
    • Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Participants without active disease in the last 5 years may be included but only after consultation with the study physician
    • Participants with celiac disease controlled by diet alone
  • History of allogenic bone marrow transplant or double umbilical cord blood transplantation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03801369


Locations
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United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Zahi Mitri, MD, MS    503-494-9160    mitri@ohsu.edu   
Principal Investigator: Zahi Mitri, MD, MS         
Salem Hospital Not yet recruiting
Salem, Oregon, United States, 97301
Contact: Janelle M. Meyer, MD    503-561-6444    jmeyer@orcancer.com   
Principal Investigator: Janelle M. Meyer, MD         
Sponsors and Collaborators
OHSU Knight Cancer Institute
AstraZeneca
National Cancer Institute (NCI)
Oregon Health and Science University
Investigators
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Principal Investigator: Zahi Mitri, MD, MS OHSU Knight Cancer Institute
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Zahi Mitri, MD, MS, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03801369    
Other Study ID Numbers: STUDY00018504
NCI-2019-00388 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00018504 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: June 29, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Durvalumab
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action