Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02899728
Recruitment Status : Suspended (Other - Pending protocol amendment Other - Pending response to FDA comments.)
First Posted : September 14, 2016
Last Update Posted : October 8, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE September 13, 2016
First Posted Date  ICMJE September 14, 2016
Last Update Posted Date October 8, 2019
Actual Study Start Date  ICMJE April 7, 2017
Estimated Primary Completion Date April 7, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
Median progression-free survival in patients who receive cediranib maleate/olaparib as maintenance therapy [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 13, 2016)
PFS rate in patients who receive cediranib maleate/olaparib as maintenance therapy as compared to standard therapy [ Time Frame: Time from initial randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 6 months ]
Change History Complete list of historical versions of study NCT02899728 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
  • Overall survival (OS) rate [ Time Frame: 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.
  • Incidence of adverse events [ Time Frame: Up to 2 years ]
    Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2016)
  • Incidence of adverse events assessed using CTCAE version 4.03 [ Time Frame: Up to 2 years ]
  • OS rate [ Time Frame: Time from initial randomization to death from any cause, assessed up to 2 years ]
Current Other Pre-specified Outcome Measures
 (submitted: April 16, 2019)
  • Blood-based angiogenic and deoxyribonucleic acid (DNA) repair biomarkers [ Time Frame: Up to 2 years ]
    Assessed by whole exome sequencing. Will be summarized using descriptive statistics.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: September 13, 2016)
  • Blood-based angiogenic and DNA repair biomarkers assessed by whole exome sequencing [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.
  • 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.
  • 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.
 
Descriptive Information
Brief Title  ICMJE Olaparib, Cediranib Maleate, and Standard Chemotherapy in Treating Patients With Small Cell Lung Cancer
Official Title  ICMJE A Phase II Study of Olaparib Plus Cediranib in Combination With Standard Therapy for Small Cell Lung Cancer
Brief 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.
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 cycles 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 cycles 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Extensive Stage Lung Small Cell Carcinoma
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Cediranib
    Given PO
    Other Name: AZD2171
  • 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
    • VP 16-213
    • VP-16
    • VP-16-213
    • VP16
  • Drug: Olaparib
    Given PO
    Other Names:
    • AZD 2281
    • AZD-2281
    • AZD2281
    • KU-0059436
    • Lynparza
    • PARP Inhibitor AZD2281
Study Arms  ICMJE
  • 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 cycles 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.

    Interventions:
    • Drug: Carboplatin
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Drug: Cisplatin
    • Drug: Etoposide
    • Drug: Olaparib
  • 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 cycles in the absence of disease progression or unacceptable toxicity.

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

    Interventions:
    • Drug: Carboplatin
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Drug: Cisplatin
    • Drug: Etoposide
    • Drug: Olaparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: September 13, 2016)
132
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 7, 2020
Estimated Primary Completion Date April 7, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02899728
Other Study ID Numbers  ICMJE NCI-2016-01363
NCI-2016-01363 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17-732
s16-01472
9974 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9974 ( Other Identifier: CTEP )
UM1CA186709 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jacob Sands Dana-Farber - Harvard Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP