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

This study is currently recruiting participants.
Verified October 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02498613
First Posted: July 15, 2015
Last Update Posted: October 20, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  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.

Condition Intervention Phase
Estrogen Receptor Negative HER2/Neu Negative Metastatic Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Progesterone Receptor Negative Stage III Breast Cancer AJCC v7 Stage III Non-Small Cell Lung Cancer AJCC v7 Stage III Pancreatic Cancer AJCC v6 and v7 Stage III Small Cell Lung Carcinoma AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Small Cell Lung Carcinoma AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Small Cell Lung Carcinoma AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7 Stage IV Non-Small Cell Lung Cancer AJCC v7 Stage IV Pancreatic Cancer AJCC v6 and v7 Stage IV Small Cell Lung Carcinoma AJCC v7 Triple-Negative Breast Carcinoma Unresectable Pancreatic Carcinoma Other: 18F-Fluoromisonidazole Drug: Cediranib Maleate Other: Laboratory Biomarker Analysis Drug: Olaparib Procedure: Positron Emission Tomography Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective response rate, measured by Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 4 weeks after completion of study treatment ]
    The exact two-sided 95% confidence interval for the objective response rate will be reported.


Secondary Outcome Measures:
  • Incidence of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 weeks after completion of study treatment ]
    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.

  • 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 ]
    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.


Other Outcome Measures:
  • Changes in level of hypoxia-related microribonucleic acids (miRNAs) (all cohorts) [ Time Frame: Baseline to post therapy ]
  • Changes in levels of angiogenesis/ inflammatory markers (angiome panel) (all cohorts) [ Time Frame: Baseline to post-therapy ]
  • Changes in tumor hypoxia by imaging, as measured by 18F-fluoromisonidazole positron emission tomography/computed tomography scans (non-small cell lung cancer) [ Time Frame: Baseline to post-cediranib monotherapy ]
    For the pre- and post-cediranib therapy outcome analysis, paired t- test or Wilcoxon signed-rank will be applied for the continuous variables.

  • Prevalence of the mutations of deoxyribonucleic acid (DNA) repair genes in each tumor cohort [ Time Frame: Up to 2 years ]
    In the first 20 endpoint-evaluable patients with non-small cell lung cancer and 20 endpoint-evaluable patients with triple negative breast cancer, the exploratory analyses will be done using Fisher's exact tests, Mann-Whitney U tests or McNemar's test depending on the type of data observed.


Estimated Enrollment: 126
Actual Study Start Date: April 26, 2016
Estimated Primary Completion Date: May 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cediranib maleate, olaparib)
Patients receive cediranib maleate PO QD. 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 course 1. Courses repeat every 28 days (35 days for course 1) in the absence of disease progression or unacceptable toxicity.
Other: 18F-Fluoromisonidazole
Correlative studies
Other Names:
  • 18F-MISO
  • 18F-Misonidazole
  • FMISO
Drug: Cediranib Maleate
Given PO
Other Names:
  • AZD2171
  • AZD2171 Maleate
  • Recentin
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281
Procedure: Positron Emission Tomography
Correlative studies
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • positron emission tomography scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging

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

IV. To evaluate levels of hypoxia-related microribonucleic acids (miRNAs) at baseline and on treatment.

OUTLINE:

Patients receive cediranib maleate orally (PO) once daily (QD). 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 course 1. 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 and then every 4 weeks thereafter.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)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 OR
  • 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; elevated thyroid stimulating hormone (TSH) with normal T3 and T4 are allowed; patients on thyroid replacement therapy are allowed
  • 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 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 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 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.; 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02498613


Locations
United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Shumei Kato    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Shumei Kato         
University of California San Diego Recruiting
San Diego, California, United States, 92103
Contact: Shumei Kato    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Shumei Kato         
UCSF Medical Center-Mount Zion Recruiting
San Francisco, California, United States, 94115
Contact: Pamela N. Munster    415-476-4082    Paul.Couey@ucsf.edu   
Principal Investigator: Pamela N. Munster         
United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Joseph W. Kim    203-785-5702      
Principal Investigator: Joseph W. Kim         
Yale University Cancer Center LAO Recruiting
New Haven, Connecticut, United States, 06520
Contact: Joseph W. Kim    203-737-6467    joseph.w.kim@yale.edu   
Principal Investigator: Joseph W. Kim         
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Joseph W. Kim    203-785-5702      
Principal Investigator: Joseph W. Kim         
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Hatem H. Soliman    800-456-7121    canceranswers@moffitt.org   
Principal Investigator: Hatem H. Soliman         
United States, Michigan
Wayne State University/Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Ulka N. Vaishampayan    313-576-9363      
Principal Investigator: Ulka N. Vaishampayan         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Dana B. Cardin    800-811-8480      
Principal Investigator: Dana B. Cardin         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Siqing Fu    713-792-3245      
Principal Investigator: Siqing Fu         
United States, Virginia
Virginia Commonwealth University/Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Sosipatros A. Boikos    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Sosipatros A. Boikos         
Canada, British Columbia
BCCA-Vancouver Cancer Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Daniel J. Renouf    888-939-3333      
Principal Investigator: Daniel J. Renouf         
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Albiruni R. Razak    416-946-4501    clinical.trials@uhn.on.ca   
Principal Investigator: Albiruni R. Razak         
Sponsors and Collaborators
National Cancer Institute (NCI)
AstraZeneca
Investigators
Principal Investigator: Joseph Kim Yale University Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02498613     History of Changes
Other Study ID Numbers: NCI-2015-01097
NCI-2015-01097 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1604017576
9881 ( Other Identifier: Yale University Cancer Center LAO )
9881 ( Other Identifier: CTEP )
P30CA016359 ( U.S. NIH Grant/Contract )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186689 ( U.S. NIH Grant/Contract )
First Submitted: July 14, 2015
First Posted: July 15, 2015
Last Update Posted: October 20, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Carcinoma
Breast Neoplasms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Pancreatic Neoplasms
Small Cell Lung Carcinoma
Triple Negative Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Digestive System Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Olaparib
Cediranib
Misonidazole
Maleic acid
Poly(ADP-ribose) Polymerase Inhibitors