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

A Phase II Study of Olaparib Plus Cediranib in Combination With Standard Therapy for Small Cell Lung Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Extensive Stage Lung Small Cell Carcinoma
• Intervention / Treatment: Drug: Carboplatin; Drug: Etoposide; Drug: Cisplatin; Drug: Olaparib; Drug: Cediranib Maleate; Drug: Cediranib

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: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 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.	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: 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: Cisplatin; Given IV; Other Names: CDDP; Cis-diamminedichloridoplatinum; Cismaplat; Cisplatinum; Neoplatin; Platinol; Abiplatin; Blastolem; Briplatin; Cis-diammine-dichloroplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; Peyrone''s Chloride; Peyrone''s Salt; Drug: Olaparib; Given PO; Other Names: Lynparza; AZD 2281; AZD-2281; AZD2281; KU-0059436; PARP Inhibitor AZD2281; Drug: Cediranib Maleate; Given PO; Other Names: AZD2171; AZD2171 Maleate; Recentin; Drug: Cediranib; Given PO; Other Names: AZD2171
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.	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: 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: Cisplatin; Given IV; Other Names: CDDP; Cis-diamminedichloridoplatinum; Cismaplat; Cisplatinum; Neoplatin; Platinol; Abiplatin; Blastolem; Briplatin; Cis-diammine-dichloroplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; Peyrone''s Chloride; Peyrone''s Salt; Drug: Olaparib; Given PO; Other Names: Lynparza; AZD 2281; AZD-2281; AZD2281; KU-0059436; PARP Inhibitor AZD2281; Drug: Cediranib Maleate; Given PO; Other Names: AZD2171; AZD2171 Maleate; Recentin; Drug: Cediranib; Given PO; Other Names: AZD2171

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Progression-free Survival in Patients Who Receive Cediranib Maleate/Olaparib as Maintenance Therapy	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.	From second randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Rate	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.	From initial randomization to death from any cause, assessed up to 2 years
Incidence of Adverse Events	Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Up to 2 years
Response Rate	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).	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood-based Angiogenic and Deoxyribonucleic Acid (DNA) Repair Biomarkers	Assessed by whole exome sequencing. Will be summarized using descriptive statistics.	Up to 2 years
Frequency of Genomic Aberrations	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.	Baseline up to 2 years
Change in Circulating Free DNA	Will be analyzed for association with patient demographics and/or disease characteristics using the Kruskal Wallis test.	Baseline up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jacob Sands, Dana-Farber - Harvard Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2018
• Primary Completion (Actual): March 17, 2020
• Study Completion (Actual): March 17, 2020

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 13, 2016
• First Posted (Estimated): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Carcinoma, Small Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Protein Kinase Inhibitors; Keratolytic Agents; Carboplatin; Etoposide; Etoposide phosphate; Cisplatin; Olaparib; Podophyllotoxin; Maleic acid; Poly(ADP-ribose) Polymerase Inhibitors; Cediranib
• Other Study ID Numbers: NCI-2016-01363 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186709 (U.S. NIH Grant/Contract); 17-732; s16-01472; 9974 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No