Olaparib, Cediranib Maleate, and Standard Chemotherapy in Treating Patients With Small Cell Lung Cancer
Condition: Extensive Stage Lung Small Cell Carcinoma
MeSH terms: Small Cell Lung Carcinoma; Carcinoma, Small Cell
Intervention: Carboplatin; Cediranib; Cediranib Maleate; Cisplatin; Etoposide; Olaparib
Intervention description: Given IV; Given PO; Given PO; Given IV; Given IV; Given PO
Intervention MeSH terms: Cisplatin; Carboplatin; Etoposide; Etoposide phosphate; Olaparib; Podophyllotoxin; Cediranib; Poly(ADP-ribose) Polymerase Inhibitors; Maleic acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well olaparib, cediranib maleate, and standard chemotherapy
      work in treating patients with small cell lung cancer. Drugs used in chemotherapy, such as
      carboplatin, cisplatin, and etoposide, work in different ways to stop the growth of tumor
      cells, either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some
      of the enzymes needed for cell growth. Olaparib, cediranib maleate, and standard chemotherapy
      may work better in treating patients with small cell lung cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of extensive-stage small cell lung
             cancer with no prior systemic treatment

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
             conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  White blood cell count (WBC) >= 3 x 10^9/L (within 28 days prior to administration of
             therapy)

          -  No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
             on peripheral blood smear (within 28 days prior to administration of therapy)

          -  Absolute neutrophil count >= 1,500/mcL (within 28 days prior to administration of
             therapy)

          -  Platelets >= 100,000/mcL (within 28 days prior to administration of therapy)

          -  Hemoglobin >= 10 g/dL with no blood transfusion within 28 days of initiation of
             therapy (within 28 days prior to administration of therapy)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
             prior to administration of therapy)

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase
             (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =<
             2.5 x institutional ULN, unless liver metastases are present and then =< 5 x
             institutional ULN is acceptable (within 28 days prior to administration of therapy)

          -  Creatinine clearance >= 50 mL/min (within 28 days prior to administration of therapy)

          -  Proteinuria - urine protein:creatinine ratio (UPC) of =< 1 OR =< 2+ proteinuria on two
             consecutive urinalysis/dipstick tests taken no less than 1 week apart; patients with
             2+ proteinuria on dipstick must also have a UPC of =< 0.5 on 2 consecutive samples
             (within 28 days prior to administration of therapy)

          -  Ability to swallow and retain oral medication

          -  The effects of olaparib and cediranib on the developing human fetus are unknown; for
             this reason and because other therapeutic agents used in this trial are known to be
             teratogenic, women of child-bearing potential and male patients and their partners who
             are sexually active must agree to use two highly effective forms of contraception in
             combination for the duration of study participation and for 3 months after completion
             of olaparib and cediranib administration; 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

          -  Postmenopausal or evidence of non-pregnant status for women of childbearing potential
             as confirmed by a negative urine or serum pregnancy test within 7 days prior to the
             start of therapy; postmenopausal status is defined as:

               -  Age >= 60 years, or

               -  Age < 60 with any one or more of the conditions below:

                    -  Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal
                       treatments,

                    -  Luteinizing hormone and/or follicle stimulating hormone and/or estradiol
                       levels in the post-menopausal range,

                    -  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)

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Participants must have archival tumor tissue available for analysis (minimum 20 5 um
             slide) or be able to undergo a baseline fresh tumor tissue biopsy

          -  Adequately controlled blood pressure; (defined as systolic blood pressure [SBP] of =<
             140 mmHg and diastolic blood pressure [DBP] of =< 90 mmHg) on maximum of three
             antihypertensive medications; participants must have a blood pressure (BP) of =<
             140/90 taken in the clinic or hospital setting by a medical professional within 2
             weeks prior to starting on study; it is strongly recommended that participants who are
             on 3 antihypertensive medications be followed by a cardiologist or a primary care
             physician for management of BP while on study

          -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction;
             patients can be on thyroid hormone replacement medication; asymptomatic patients with
             elevated thyroid stimulating hormone (TSH) with normal T4/T3 are allowed to enroll,
             and recommended to follow with routine thyroid function test

        Exclusion Criteria:

          -  Patients who have had major surgery or trauma within 28 days prior to entering the
             study; patients must have recovered from any effects of any major surgery and surgical
             wound should have healed prior to starting treatment

          -  Patients who have had radiotherapy within 14 days prior to entering the study

          -  Patients with a non-healing wound, fracture, or ulcer

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > Common Terminology Criteria for Adverse Events
             [CTCAE] grade 1 or baseline, with the exception of alopecia)

          -  Patients who are receiving any other investigational agents

          -  Patients with symptomatic central nervous system (CNS) metastases or leptomeningeal
             carcinomatosis should be excluded from this clinical trial because of their poor
             prognosis and because they often develop progressive neurologic dysfunction that would
             confound the evaluation of neurologic and other adverse events; exceptions include
             patients with previously-treated CNS metastases or those with are asymptomatic,
             subcentimeter metastases, and have no requirement for steroids or anti-seizure
             medication for at least one week prior to study entry; screening with CNS imaging
             studies (CT scan or MRI) is required

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to olaparib, cediranib, carboplatin, cisplatin, or etoposide

          -  Patients with a history of myelodysplastic syndrome (MDS)

          -  Patients with a history of acute myeloid leukemia (AML), or patients with a history of
             any other primary malignancy within 3 years prior to initiation of treatment on this
             study; exceptions include: patients with a history of malignancies (other than AML)
             that were treated curatively and have not recurred within 3 years prior to study
             entry; resected basal and squamous cell carcinomas of the skin; and completely
             resected carcinoma in situ of any type

          -  Patients with clinically significant gastrointestinal abnormalities including, but not
             limited to:

               -  Clinically significant signs and/or symptoms of bowel obstruction within 3 months
                  prior to starting treatment

               -  History of intra-abdominal abscess within 3 months prior to starting treatment

               -  History of gastrointestinal (GI) perforation within 6 months prior to starting
                  treatment

               -  Evidence of abdominal fistula within 6 months prior to starting treatment;
                  history of abdominal fistula will be considered eligible if the fistula was
                  surgically repaired, and there has been no evidence of fistula for at least 6
                  months prior to starting treatment, and patient is deemed to be at low risk of
                  recurrent fistula

          -  Patients with a history of cerebrovascular accident including transient ischemic
             attack (TIA), pulmonary embolism or insufficiently treated deep venous thrombosis
             (DVT) within the past 3 months; Note: Participants with recent DVT who have been
             treated with therapeutic anti-coagulants for at least 6 weeks are eligible, with the
             exception of participants being treated with warfarin, which is prohibited on this
             study; other oral anti-coagulants may be allowed after discussion with overall
             principal investigator (PI), but short half-life low molecular weight heparins are
             strongly preferred

          -  Patients with evidence of active bleeding diathesis

          -  Patients with hemoptysis in excess of 2.5 mL within 6 weeks prior to the first dose of
             study medication

          -  Patients receiving any medications or substances that are potent inhibitors or
             inducers of CYP3A4 are ineligible; the required washout period for strong inhibitors
             is 2 weeks and at least one week for moderate inhibitors; the required washout period
             prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 4 weeks
             for other agents

          -  Patients requiring concomitant therapy with phenytoin, phenobarbital, carbamazepine,
             or valproic acid

          -  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; specifically, patients with any of the following within 6 months
             prior to starting treatment are excluded:

               -  Acute myocardial infarction

               -  Unstable angina

               -  New York Heart Association functional classification of III or IV

               -  Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per
                  institutional guidelines, or 55%

               -  Prior allogeneic bone marrow transplant or double umbilical cord blood
                  transplantation

               -  Patients with active hepatitis (B or C)

               -  Patients with active pneumonitis

          -  Pregnant women are excluded from this study because olaparib and cediranib are agents
             with the potential for teratogenic or abortifacient effects; because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with olaparib or cediranib, breastfeeding should be
             discontinued if the mother is treated with olaparib or cediranib; these potential
             risks may also apply to other agents used in this study

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             olaparib and cediranib; in addition, these patients are at increased risk of lethal
             infections when treated with marrow-suppressive therapy; appropriate studies will be
             undertaken in patients receiving combination antiretroviral therapy when indicated

          -  Patients must be willing and able to check and record daily blood pressure readings if
             receiving cediranib