Patient case: 45-year-old female with cervical cancer; genetic feature: ERBB2 (S310Y)

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

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). 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.

Eligibility: 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

Relevance to patient case: not relevant