Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: OLAParib COmbinations

Summary: The primary objective of this phase II trial is to determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.

Detailed description: This is a phase II signal-searching study in a range of tumor types with the potential to identify novel tumor indications for combination therapy with olaparib that can subsequently be explored in dedicated studies. Patients will be enrolled in this study based on molecular markers from genetic profiling performed on their tumors prior to study entry (outside of protocol). The trial will also identify genetic determinants of response and resistance.
  Patients with tumors harboring mutations in DNA damage repair genes will be treated with olaparib. Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. Patients with tumors harboring PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib. Patients with tumors harboring mutations such as TORC1/2 or TSC1/2 or LKB1 mutations or are PTEN-deficient (determined either by genetic mutation or by IHC) will be treated with AZD2014 plus olaparib.

Eligibility: Inclusion Criteria:
  -  Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
  -  Patients who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible patients should not have available therapies that will convey clinical benefit.
  -  Progressive cancer at the time of study entry
  -  Measurable disease by RECIST v1.1
  -  Age ≥ 18 years
  -  Life expectancy ≥ 16 weeks
  -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (APPENDIX A: Performance Status Criteria)
  -  Able to understand the nature of this trial and provide written informed consent
  -  Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  -  Molecular testing results from CLIA-certified laboratories used for patient eligibility should be obtained from the most recent tumor biopsy (baseline tumor biopsies and on-progression tumor biopsies are optional)
  -  No previous treatment with the specific assigned study drug or any other drug sharing the same target. Prior treatment in monotherapy when treated in one of the combination arms in the study is allowed.
  -  Prior radiation therapy is allowed. Patients must not have received radiation therapy within 4 weeks prior to the initiation of study treatment.
  -  Other therapies: Prior experimental (non-FDA approved) therapies (other than drugs that share the same target) and immunotherapies are allowed. Patients must not have received these therapies for 30 days or five half-lives of the drug (whichever is less) prior to the initiation of study treatment and must have full recovery from any acute effects of these therapies.
  -  Adequate hematologic function defined as:
  -  Absolute neutrophil count (ANC) ≥ 1500/μL
  -  White blood cells (WBC) > 3x109/L
  -  Hemoglobin (Hgb) ≥ 10 g/dL (may be achieved with erythropoietin agents; no blood transfusions in the 28 days prior to entry)
  -  Platelets ≥ 100,000/μL
  -  No features suggestive of MDS/AML on peripheral blood smear
  -  Adequate renal and liver function defined as:
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) (≤ 5 × ULN if considered due to primary or metastatic liver involvement)
  -  Total bilirubin ≤ 1.5 ×ULN
  -  Alkaline phosphatase ≤ 2× ULN (≤ 5 × ULN if considered due to tumor)
  -  Serum creatinine ≤ 1.5 ULN
  -  At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm with calipers by clinical exam OR At least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/plain x-ray/clinical exam at baseline and follow up visits.
  -  Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to adequate birth control if conception is possible during the study and for 6 months after the last dose. Female patients are considered to not be of child-bearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 1 year without menses.
  Exclusion Criteria:
  -  Patients with known germline BRCA mutations will be excluded from the study, however testing is not required for inclusion in the study.
  -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  -  Previous enrolment in the present study
  -  Participation in another clinical study with an investigational product during the last 30 days or five half-lives of the drug (whichever is greater) prior to the initiation of study treatment.
  -  Prior treatment with the same agent or combination as the study drug. Prior treatment in monotherapy when treated in one of the combination arms in the study is allowed.
  -  Patients with hematologic malignancies (includes patients with myelodysplastic syndrome/acute myeloid leukemia).
  -  Patients must not have received allogeneic stem cell transplant
  -  Concurrent administration of any other anti-cancer therapy
  -  Bisphosphonates and Denosumab for bone metastases are allowed as long as these were started at least 4 weeks prior to treatment with study drug.
  -  Octreotide is allowed if dose is stable for >3 months with no worsening of carcinoid syndrome
  -  Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant prostate cancer is permitted
  -  Most recent chemotherapy within 3 weeks prior to entering the study
  -  Therapeutic radiotherapy within the previous 3 weeks if ≤5% of their total marrow volume or 4 weeks if >5% of their total marrow volume, or unresolved acute or subacute toxicities from prior radiotherapy.
  -  Most recent experimental (non-FDA approved) anti-cancer therapy or immunotherapies ≤ 30 days or five half-lives of the drug (whichever is less)
  -  Patients who have not recovered to ≤ CTCAE grade 1 toxicities related to prior therapy (administered more than 3 weeks earlier) or incomplete recovery from previous surgery, unless agreed by the Principal Investigator (PI) and documented are not eligible to participate in this study with the exception of grade 2 peripheral neuropathy if it has been stable, and not worsening, for at least 28 days, and grade 2 alopecia.
  -  Persistent toxicities (≥CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy.
  -  Active or untreated brain metastases or spinal cord compression
  -  A scan to confirm the absence of brain metastases is not required.
  -  Patients with treated brain metastases or spinal cord compression are eligible if they have minimal neurologic symptoms and evidence of stable disease (for at least 1 month) or response on follow-up scan. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.
  -  History of carcinomatous meningitis
  -  Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
  -  Patient must not have a co-morbid condition(s) that, in the opinion of the investigator, prevent safe treatment.
  -  Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy (testing is not part of the protocol).
  - Patients with known (testing is not part of the protocol) active hepatic disease (i.e., Hepatitis B or C) due to risk of drug interactions with anti-viral therapy.
  -  Any of the following cardiovascular events within 6 months prior to study entry: myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart failure, cerebral vascular accident, or transient ischemic attack
  -  History or presence of clinically significant ventricular or atrial dysrhythmia > Grade 2 (NCI CTCAE v4.0)
  − Patients with chronic, rate-controlled atrial arrhythmias who do not have other cardiac abnormalities are eligible.
  -  Major surgery within 3 weeks prior to first dose of study treatment, and patients must have recovered from the effects of surgery
  -  Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  -  Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption
  -  Patients with uncontrolled seizures
  -  Inadequate bone marrow reserve within past 28 days prior to study treatment as demonstrated by:
  -  Absolute neutrophil count (ANC) < 1500/μl,
  -  WBC ≤ 3x109/L
  -  Platelet count (PLT) < 100,000/μl, or
  -  Hemoglobin (Hgb) < 10 g/dL
  -  Blood (packed red blood cells, platelets) transfusions within 1 month prior to study start
  -  whole blood transfusion in the last 120 days prior to entry to the study
  -  Patients with concomitant use of drugs, herbal supplements and/or ingestion of foods known to modulate CYP3A4 enzyme activity
  -  Please refer to APPENDIX B: LIST OF CYP3A4 INHIBITORS AND INDUCERS
  -  Please refer to appendices for olaparib (APPENDIX C) and AZD5363 plus olaparib (APPENDIX D) for a more comprehensive list for each respective drug
  -  Women who are pregnant or lactating (breastfeeding)
  -  Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
  -  Patients with a known hypersensitivity to the combination/comparator agent
  -  Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results
  − Patients 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, superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent
  -  Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Relevance to patient case: not relevant