Patient case: 52-year-old male with Lung cancer. Genetic variant: EML4-ALK Fusion transcript. Other conditions: Hypertension, Osteoarthritis.

Clinical trial: A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors

Summary: This phase II trial studies cediranib maleate in combination with olaparib in treating patients with solid tumors that have spread to other parts of the body or cannot be removed by surgery, including breast cancer, non-small cell lung cancer, small cell lung cancer, and pancreatic cancer. Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate may also block the flow of oxygen to the tumor, and may help make the tumor more sensitive to olaparib.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the objective response rate (ORR) of cediranib (cediranib maleate) plus olaparib in combination in patients with advanced or metastatic solid tumors of the following tumor types: non-small cell lung cancer (NSCLC), germline breast cancer, early onset 1/2 (BRCA1/2) wild type (wt), basaloid triple negative breast cancer (b-TNBC), pancreatic ductal adenocarcinoma (PDAC), and small cell lung cancer (SCLC). The responses will be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  SECONDARY OBJECTIVES:
  I. To assess the safety and tolerability of oral administration of cediranib in combination with olaparib in patients with select advanced solid tumors.
  II. To determine progression free survival (PFS) in each tumor cohort.
  TERTIARY OBJECTIVES:
  I. To estimate the prevalence of the mutations of deoxyribonucleic acid (DNA) repair genes in tumors using the BROCA panel and to correlate tumor regression with mutations status. (Integrated) II. To evaluate changes in tumor hypoxia on cediranib treatment compared to baseline by [F-18] fluoromisonidazole (FMISO) positron emission tomography/computed tomography (PET/CT) in patients with NSCLC.
  III. To evaluate BRCA1 expression in patients with NSCLC or basaloid TNBC at baseline and changes on 4 days of cediranib treatment in the NSCLC and TNBC cohorts.
  IV. To evaluate hypoxia markers at baseline and changes on treatment with cediranib in tumor tissue in the NSCLC and TNBC cohorts.
  V. To evaluate levels of angiogenesis/inflammatory markers including VEGF at baseline and on treatment.
  VI. To evaluate levels of hypoxia-related microribonucleic acids (miRNAs) at baseline and on treatment.
  OUTLINE:
  Patients receive cediranib maleate orally (PO) once daily (QD) for 3-4 days and then undergo biopsy. After biopsy, patients continue to receive cediranib maleate PO QD and begin olaparib PO twice daily (BID) beginning on the day after the post-dose biopsy (days 4-7) or by day 8 of course 1 (biopsy cohorts-NSCLC and TNBC) or day 4 of course 1 (non-biopsy cohorts-PDAC and SCLC). Courses repeat every 28 days (35 days for course 1) in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up for 4 weeks.

Eligibility: Inclusion Criteria:
  -  Patients must have histologically confirmed, metastatic or unresectable malignancy of the following types: (a) non-squamous, non-small cell lung cancer (NSCLC), (b) triple-negative breast cancer (TNBC; defined by estrogen receptor [ER] < 1%, progesterone receptor [PR] < 1% and human epidermal growth factor receptor 2 f[HER2] immunohistochemistry [IHC]: 1+ or less; if 2+, a negative fluorescence in situ hybridization [FISH] testing is required) without germline BRCA mutation, (c) pancreatic adenocarcinoma (PDAC), or (d) small cell lung cancer (SCLC)
  -  For NSCLC patients only:
  -  Must be willing to undergo paired FMISO PET scans (the first 20 evaluable patients only)
  -  Must be willing to undergo paired biopsies (the first 20 evaluable patients only)
  -  Must have progressive disease after platinum-based regimen and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(s) (TKI[s]) or anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors if sensitizing mutations are present
  -  For TNBC patients only
  -  Must be known germline BRCA wild-type; BRCA mutation carriers are excluded; if unknown, then BRCA testing must be performed in a clinical Clinical Laboratory Improvement Amendments (CLIA) certified lab
  -  Must have basaloid subtype TNBC as determined by research PAM-50 test
  -  Must have tumor amenable for, and be willing to undergo, baseline and on-treatment biopsies (the first 20 evaluable patients only)
  -  Must have received at least 1 prior chemotherapy regimen in the metastatic setting
  -  For PDAC patients only
  -  Must have received at least one standard chemotherapy either with or without radiation therapy based on the institution's standard of care
  -  For SCLC patients only
  -  Must have had a standard platinum-based regimen for limited or extensive stage disease
  -  FOR ALL PATIENTS
  -  Patients must have measurable disease by RECIST v1.1
  -  Toxicities of prior therapy (except alopecia) should be resolved to =< grade 1 as per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0; patients with long-standing stable grade 2 neuropathy may be considered after discussion with the study principal investigator (PI)
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  -  Life expectancy of >= 4 months
  -  Leukocytes >= 3,000/mcL
  -  Absolute neutrophil count >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Hemoglobin > 9 g/dL
  -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  -  Creatinine =< 1.5 x ULN
  -  Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  -  A urine protein:creatinine ratio of < 1 or <1 g protein on 24-hour urine collection
  -  International normalized ration (INR) within 1.25 x ULN institutional limits, except where a lupus anti-coagulant has been confirmed
  -  Activated partial thromboplastin time (aPTT) within 1.25 x ULN institutional limits, except where a lupus anti-coagulant has been confirmed
  -  Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
  -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid stimulating hormone (TSH) within normal limits
  -  Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic) taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients with hypertension may be managed with up to a maximum of 3 antihypertensive medications; patients who are on 3 antihypertensive medications are highly recommended to be followed by a cardiologist or blood pressure specialist for management of BP while on protocol
  -  Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities, and must have documented left ventricular ejection fraction (LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months
  -  Prior treatment with anthracyclines
  -  Prior treatment with trastuzumab
  -  A New York Heart Association (NYHA) classification of II controlled with treatment
  -  Prior central thoracic radiation therapy (RT), including RT to the heart
  -  History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study)
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of cediranib and olaparib administration
  -  Ability to understand and the willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Patients with known deleterious BRCA germline mutation by standard clinical testing are excluded; for TNBC patients, BRCA germline testing is required, if not performed previously; for the other cohorts, BRCA germline testing is not required
  -  Patients who have had chemotherapy or RT within 3 weeks prior to start of the study agents, or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
  -  Patients should not have received any other investigational agents within the past 4 weeks
  -  Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should be excluded from this clinical trial; screening Brain MRI will be required for patients with recurrent NSCLC, TNBC, or SCLC; brain MRI is required for PDAC if clinically suspected by patient's symptoms or neurological exam. Should patient found to have brain metastasis, treatment of brain metastasis must precede the participation in this study; for patients with known and treated brain metastases is allowed in this study if they fulfill the following criteria:
  -  The lesions have improved or remained stable radiographically and clinically for at least 6 weeks after completion of brain irradiation or stereotactic brain radiosurgery and off steroids for at least 6 weeks
  -  Patients who have received prior inhibitor of VEGF signaling and a poly (ADP-ribose) polymerases (PARP) inhibitor administered in combination; unless administered in combination, patients who received a prior PARP inhibitor or a prior VEGF-signaling inhibitor agent are allowed after discussing with the PI
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib or olaparib
  -  Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension
  -  Current use of natural herbal products or other "folk remedies"
  -  Patients with concomitant or prior invasive malignancies within the past 3 years; subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  -  History of myocardial infarction within 6 months
  -  History of stroke or transient ischemic attack within 6 months
  -  NYHA classification of III or IV
  -  Current condition requiring concurrent use of drugs or biologics with anti-arrhythmic or pro-arrhythmic potential
  -  History of hypertensive crisis or hypertensive encephalopathy within 3 years
  -  Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm (> 5 cm) or aortic dissection); if known history of abdominal aortic aneurysm with > 4cm in diameter, all of the following must be met:
  -  An ultrasound (US) within the last 6 months will be required to document that it is < 5cm
  -  Patient must be asymptomatic from the aneurysm
  -  Blood pressure must be well controlled as defined in this protocol
  -  A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib (percutaneous/endobronchial biopsies are allowed)
  -  Patients may not have current signs and/or symptoms of bowel obstruction within 1 month prior to starting study drugs, except if it was a temporary incident (improved within < 24 hrs with medical management)
  -  History of hemoptysis or any significant bleeding within the last 1 month prior to enrollment
  -  Presence of cavitation of central pulmonary lesion
  -  History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation within the 3 months prior to enrollment
  -  Patients may not have current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
  -  Patients may not have evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted; the clinical indication for therapeutic anticoagulation must be clearly documented prior to enrollment and must be discussed with the P.I.; given the increased risk of serious bleeding from cediranib, patients who are on greater than or equal to 2 anti-thrombotic agents, including but not limited to anti-platelet agents (non-steroidal anti-inflammatory drugs [NSAIDs]/aspirin, clopidogrel), heparin, low molecular weight heparin [LMWH], warfarin, and a direct thrombin inhibitor, will be excluded
  -  Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
  -  Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cediranib and olaparib
  -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  -  Any condition that, in the opinion of the treating investigator would interfere with evaluation of the investigational product or interpretation of subject safety or study results

Relevance to patient case: not relevant