Clinical Trials /

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

NCT02498613

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Adenocarcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors
  • Official Title: A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01097
  • SECONDARY ID: NCI-2015-01097
  • SECONDARY ID: 1604017576
  • SECONDARY ID: 9881
  • SECONDARY ID: 9881
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02498613

Conditions

  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Metastatic Pancreatic Adenocarcinoma
  • Pancreatic Ductal Adenocarcinoma
  • Progesterone Receptor Negative
  • Stage III Breast Cancer AJCC v7
  • Stage III Lung Non-Small Cell Cancer AJCC v7
  • Stage III Lung Small Cell Carcinoma AJCC v7
  • Stage III Pancreatic Cancer AJCC v6 and v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIA Lung Small Cell Carcinoma AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIB Lung Small Cell Carcinoma AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IV Breast Cancer AJCC v6 and v7
  • Stage IV Lung Non-Small Cell Cancer AJCC v7
  • Stage IV Lung Small Cell Carcinoma AJCC v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
  • Triple-Negative Breast Carcinoma
  • Unresectable Pancreatic Carcinoma

Interventions

DrugSynonymsArms
CediranibAZD2171Treatment (cediranib maleate, olaparib)
Cediranib MaleateAZD2171, AZD2171 Maleate, RecentinTreatment (cediranib maleate, olaparib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (cediranib maleate, olaparib)

Purpose

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), triple negative breast cancer (TNBC),
      pancreatic ductal adenocarcinoma (PDAC), and small cell lung cancer (SCLC).

      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 estimate progression free survival (PFS) in each tumor cohort.

      EXPLORATORY 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 levels of angiogenesis/inflammatory markers including VEGF at baseline and
      on treatment.

      IV. To evaluate levels of circulating tumor deoxyribonucleic acid (ctDNA) at baseline and on
      treatment.

      OUTLINE:

      Patients receive cediranib maleate orally (PO) once daily (QD) on day 1. Patients undergoing
      FMISO scan also receive olaparib PO twice daily (BID) beginning the day after the second
      FMISO scan and the rest of the patients receive olaparib PO BID beginning day 4 of cycle 1.
      Cycles repeat every 28 days (35 days for cycle 1) in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 4 weeks and then every 4
      weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cediranib maleate, olaparib)ExperimentalPatients receive cediranib maleate PO QD on day 1. Patients undergoing FMISO scan also receive olaparib PO BID beginning the day after the second FMISO scan and the rest of the patients receive olaparib PO BID beginning day 4 of cycle 1. Cycles repeat every 28 days (35 days for cycle 1) in the absence of disease progression or unacceptable toxicity.
  • Cediranib
  • Cediranib Maleate
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed, metastatic or unresectable malignancy of
             the following types: (a) non-small cell lung cancer (NSCLC), (b) triple-negative
             breast cancer (TNBC; defined by estrogen receptor [ER] < 1%, progesterone receptor
             [PR] < 1% and HER2 1+ or less by immunohistochemistry [IHC]; if HER-2 expression is
             2+, a negative fluorescence in situ hybridization [FISH] testing is required) (c)
             pancreatic adenocarcinoma (PDAC), or (d) small cell lung cancer (SCLC)

          -  Must have received at least one line of standard systemic treatment for locally
             advanced or metastatic disease setting of the respective tumor type; for NSCLC, it is
             either PD-1/PD-L1 inhibitor, or platinum-containing chemotherapy, or an EGFR tyrosine
             kinase inhibitor or an ALK inhibitor if sensitizing mutation present; TNBC:
             platinum-containing chemotherapy; PDAC: fluorouracil (5-FU-), gemcitabine-, or
             taxane-containing chemotherapy either with or without radiation therapy; SCLC:
             platinum-containing chemotherapy for limited or extensive stage disease

          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) version (v)1.1

          -  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)5.0; patients with long-standing stable grade 2 neuropathy or prior grade 2
             treatment-related hypothyroidism requiring treatment, provided free T4 within normal
             range, may be considered eligible after discussion with the study principal
             investigator (PI)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Karnofsky >=
             50%)

          -  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 OR

          -  Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above
             institutional normal; the creatinine clearance is calculated using Cockcroft-Gault
             formula

          -  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 defined by free T4 within normal range, with no
             symptoms of thyroid dysfunction

          -  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)

          -  The effects of cediranib and olaparib on the developing human fetus are unknown; for
             this reason, 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 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, since neurologic dysfunction may confound the evaluation of neurologic and
             other adverse events (AEs); screening brain MRI (or CT if MRI contraindicated) will be
             required for patients with recurrent NSCLC, TNBC, or SCLC; brain MRI (or CT if MRI
             contraindicated) 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 complementary alternative medications
             (CAM) or "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 prior to registration

          -  History of stroke or transient ischemic attack within 6 months prior to registration

          -  NYHA classification of III or IV

          -  Current cardiac arrhythmia requiring concurrent use of anti-arrhythmic drugs

          -  History of hypertensive crisis or hypertensive encephalopathy within 3 years prior to
             registration

          -  Clinically significant peripheral vascular disease or abdominal aortic aneurysm (> 5
             cm) or aortic dissection; if known history of abdominal aortic aneurysm with >= 4 cm
             in diameter, all of the following must be met:

               -  An ultrasound (US) within the last 6 months prior to registration will be
                  required to document that it is =< 5 cm

               -  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)

          -  History of bowel obstruction within 1 month prior to starting study drugs

          -  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 increases 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 because olaparib and cediranib have the
             potential for teratogenic or abortifacient effects; due to the fact that there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with olaparib and cediranib, 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 because of the potential for pharmacokinetic interactions with
             cediranib or olaparib; appropriate studies will be undertaken in patients receiving
             combination antiretroviral therapy when indicated; HIV-positive patients with
             undetectable viral loads and CD4 counts > 300, and not on any antiretroviral therapy
             may be allowed after discussing with the principle investigator

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 4 weeks after completion of study treatment
Safety Issue:
Description:Measured by Response Evaluation Criteria in Solid Tumors version 1.1. The exact two-sided 95% confidence interval for the objective response rate will be reported.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 4 weeks after completion of study treatment
Safety Issue:
Description:Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percentages and frequencies for categorical parameters, will be presented. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 3 and grade 4 laboratory abnormalities will be listed.
Measure:Progression-free survival
Time Frame:The duration of time from start of treatment to time of progression or death, whichever occurs first, assessed up to 4 weeks after completion of study treatment
Safety Issue:
Description:Estimated using the Kaplan-Meier method with the 95% confidence intervals. Thomas and Grunkemeier confidence interval will be reported. The possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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