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Olaparib, Cediranib Maleate, and Standard Chemotherapy in Treating Patients With Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT02899728
Recruitment Status : Suspended (Other - Pending protocol amendment)
First Posted : September 14, 2016
Last Update Posted : December 4, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized 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.

Condition or disease Intervention/treatment Phase
Extensive Stage Lung Small Cell Carcinoma Drug: Carboplatin Drug: Cediranib Maleate Drug: Cisplatin Drug: Etoposide Other: Laboratory Biomarker Analysis Drug: Olaparib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether the addition of cediranib maleate (cediranib) plus olaparib as maintenance therapy, in patients with small cell lung cancer (SCLC) who have stable disease or better (non-progressive disease or non-PD) after initial therapy, leads to improved median progression-free survival (PFS), PFS is measured in months from the time of randomization to maintenance therapy (after completion of initial therapy), compared to standard therapy (no maintenance treatment.

SECONDARY OBJECTIVES:

I. To evaluate the impact of cediranib plus olaparib maintenance therapy on median overall survival (OS) in patients with SCLC who have non-PD after initial therapy.

II. To determine whether the addition of cediranib to cisplatin/carboplatin plus etoposide during initial therapy adds benefit to response rate, median PFS and median OS.

III. To assess safety and tolerability of the combination of cediranib plus olaparib during maintenance therapy.

IV. To evaluate potential biomarkers of clinical benefit to olaparib/cediranib combination, including tumor proteomic and genomic markers, and circulating levels of cytokines and angiogenic factors, that that may be associated with clinical benefit.

OUTLINE:

INITIAL THERAPY PHASE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive carboplatin intravenously (IV) over 60 minutes or cisplatin IV over 60 minutes on day 1 and etoposide IV over 60 minutes on days 1, 2, and 3. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive treatment as in Arm I and also receive cediranib maleate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients in Arm I who have stable disease, partial, or a complete response are randomized to receive maintenance therapy or no maintenance therapy. Patients in Arm II are assigned to receive maintenance therapy.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO twice daily (BID) on days 1-28.

NO MAINTENANCE THERAPY: Patients are eligible to crossover to receive treatment with cediranib maleate and olaparib upon disease progression at the treating investigator's discretion.

After completion of study treatment, patients are followed up every 3-4 months for at least 1 year.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Olaparib Plus Cediranib in Combination With Standard Therapy for Small Cell Lung Cancer
Actual Study Start Date : April 7, 2017
Estimated Primary Completion Date : April 7, 2020
Estimated Study Completion Date : April 7, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Arm I (chemotherapy, cediranib maleate, olaparib)

Patients receive carboplatin IV over 60 minutes or cisplatin IV over 60 minutes on day 1 and etoposide IV over 60 minutes on days 1, 2, and 3. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients in Arm I who have stable disease, partial, or a complete response are randomized to receive maintenance therapy or no maintenance therapy. Patients in Arm II are assigned to receive maintenance therapy.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28.

NO MAINTENANCE THERAPY: Patients are eligible to crossover to receive treatment with cediranib maleate and olaparib upon disease progression at the treating investigator's discretion.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Cediranib Maleate
Given PO
Other Names:
  • AZD2171
  • AZD2171 Maleate
  • Recentin

Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Experimental: Arm II (chemotherapy, cediranib maleate, olaparib)

Patients receive treatment as in Arm I and also receive cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for up to 4 courses in theabsence of disease progression or unacceptable toxicity..

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Cediranib Maleate
Given PO
Other Names:
  • AZD2171
  • AZD2171 Maleate
  • Recentin

Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. PMedian progression-free survival (PFS) in patients who receive cediranib maleate/olaparib as maintenance therapy [ Time Frame: Time from second randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 6 months ]
    Will be compared to those receiving standard therapy. will use the intention-to-treat framework in which all patients randomized are considered recipients of their randomized assignment, regardless of treatment actually received.


Secondary Outcome Measures :
  1. Overall survival (OS) rate [ Time Frame: Time from initial randomization to death from any cause, assessed up to 2 years ]
    Additional sensitivity analyses will be conducted on OS to address the effect of potential crossover to olaparib/cediranib on overall survival estimates. These will include rank preserving structural failure time models.

  2. Incidence of adverse events assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 2 years ]
  3. Response rate [ Time Frame: Up to 2 years ]
    Rates in each arm will be provided with exact 95% confidence intervals, and compared using the chi-squared test (or Fisher's exact test, as needed).


Other Outcome Measures:
  1. Blood-based angiogenic and deoxyribonucleic acid (DNA) repair biomarkers assessed by whole exome sequencing [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  2. Frequency of genomic aberrations [ Time Frame: Baseline up to 2 years ]
    Will be assessed using McNemar's test and Fisher's exact test. More sophisticated analyses may include multivariable logistic regression modeling and/or competing risks analysis.

  3. Change in circulating free DNA [ Time Frame: Baseline up to 2 years ]
    Will be analyzed for association with patient demographics and/or disease characteristics using the Kruskal Wallis test.



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, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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
  • Urine protein: creatinine ratio (UPC) of =< 1; UPC is the preferred test
  • Ability to swallow and retain oral medication
  • 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 principle 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; breastfeeding should be discontinued if the mother is treated with olaparib or cediranib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients must be willing and able to check and record daily blood pressure readings if receiving cediranib

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): NCT02899728


Locations
United States, California
Los Angeles County-USC Medical Center
Los Angeles, California, United States, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
Keck Medical Center of USC Pasadena
Pasadena, California, United States, 91105
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Georgia
Emory University Hospital Midtown
Atlanta, Georgia, United States, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Kentucky
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States, 40536
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, United States, 63141
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Siteman Cancer Center at Christian Hospital
Saint Louis, Missouri, United States, 63136
Siteman Cancer Center at Saint Peters Hospital
Saint Peters, Missouri, United States, 63376
United States, New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, United States, 10016
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States, 19107
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
United States, Virginia
University of Virginia Cancer Center
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Leena Gandhi Laura and Isaac Perlmutter Cancer Center at NYU Langone EDDOP

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02899728     History of Changes
Other Study ID Numbers: NCI-2016-01363
NCI-2016-01363 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s16-01472
9974 ( Other Identifier: Laura and Isaac Perlmutter Cancer Center at NYU Langone EDDOP )
9974 ( Other Identifier: CTEP )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Small Cell Lung Carcinoma
Carcinoma, Small Cell
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Etoposide phosphate
Olaparib
Cediranib
Cisplatin
Carboplatin
Etoposide
Podophyllotoxin
Maleic acid
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Protein Kinase Inhibitors