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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2026
  • participants needed
    28
  • sponsor
    OHSU Knight Cancer Institute
Updated on 10 March 2022
estrogen
progesterone
immunohistochemistry
HER2
triple negative breast cancer
progesterone receptor
erbb2
estrogen receptor

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.

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.

Details
Condition Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma, Prognostic Stage IV Breast Cancer AJCC v8
Treatment durvalumab, olaparib, Durvalumib
Clinical Study IdentifierNCT03801369
SponsorOHSU Knight Cancer Institute
Last Modified on10 March 2022

Eligibility

Yes No Not Sure

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
Prior therapies for metastatic breast cancer
Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 that is amenable
Frontline patients who have not received prior systemic therapy for metastatic breast cancer are eligible
to biopsy
Patients who have received =< 2 prior chemotherapy regimens for metastatic breast cancer are eligible
Participants must have a life expectancy >= 16 weeks
Participant must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Participants must have fully recovered from the acute toxic effects of all prior
Participant must consent to undergo a pre-treatment screening biopsy for enrollment and subsequent biomarker analyses
treatment to grade 1 or less, except alopecia and =< grade 2 neuropathy which
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
are allowed
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
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)
Participants must not have received previous treatment with PARP inhibitors, including
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)
olaparib
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)
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
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

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
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 infection including tuberculosis (clinical evaluation that includes clinical
criterion
history, physical examination and radiographic findings, and tuberculosis [TB]
Participants with vitiligo or alopecia
testing in line with local practice), hepatitis B (known positive hepatitis B
Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human
Any chronic skin condition that does not require systemic therapy
immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2
Participants without active disease in the last 5 years may be included but only after consultation with the study physician
antibodies). Participants with a past or resolved HBV infection (defined as
Participants with celiac disease controlled by diet alone
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)
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
History of allogenic bone marrow transplant or double umbilical cord blood
transplantation
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