Clinical trial NCT02038647: Phase 2 Study of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)
Official title: A Randomized, Double-blind, Placebo-controlled, Phase 2 Clinical Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Small Cell Lung Cancer
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-01-16
Enrollment: 178
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a two-arm, randomized, double-blind, placebo-controlled, multicenter, phase 2 study designed to is to determine if the combination treatment can improve progression free survival (defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first) when compared with placebo + paclitaxel.

Detailed description: The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have Small Cell Lung Cancer (SCLC). This study determined the safety and efficacy for alisertib when given twice a day along with paclitaxel.

This open label study enrolled 178 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) and participants were stratified at baseline as to whether brain mets were present or not; whether they were sensitive to prior therapy or were relapsed/refractory to prior therapy; and by world region:

* Alisertib 40 mg + Paclitaxel 60 mg/m\^2
* Paclitaxel 80 mg/m\^2 + Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.

This multi-center trial was conducted world-wide. The overall time to participate in this study was approximately up to 22 months. Participants made multiple visits to the clinic, and were contacted by telephone every month for 6 months after the end of treatment (EOT) for follow-up assessment of progression free survival and for overall survival every 2 months until death, study closure, or 14 months after randomization of the last participant.

Eligibility criteria: Inclusion Criteria

Each participant must meet all the following inclusion criteria to be enrolled in the study:

1. Male or female participants ≥ 18 years old.
2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.
3. Have received and progressed after a platinum-based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES).
4. Have measurable disease within ≤ 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0-1).
6. Participants with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the participant is off steroids or is on a stable dose of steroids. Participants should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs.

Exclusion Criteria

Participants meeting any of the following exclusion criteria are not to be randomized to treatment:

1. Any prior therapy for second-line treatment of SCLC.
2. Participants who relapsed ≥ 180 days after their response to first-line treatment.
3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib, or any other investigational agent.
4. Prior treatment with paclitaxel or any other taxane agent.
5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.
6. Any comorbid condition or unresolved toxicity that would preclude administration of alisertib or weekly paclitaxel.
7. Prior history of ≥ Grade 2 neurotoxicity that is not resolved to ≤ Grade 1.
8. Participants with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.
9. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during study conduct. Major prohibited enzyme inducers include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John's wort.
10. Inability to swallow alisertib or other orally administered medications.
11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or pancreatic enzymes.
12. Diagnosed with or treated for another malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease.
13. Other severe acute or chronic medical or psychiatric condition(s) per protocol.
14. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of Grade \> 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug.
15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.
16. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status.
17. Participants who are pregnant, lactating, or do not agree to use effective methods of contraception during the study treatment period through 6 months after the last dose of study drug per protocol.

Primary outcomes:
measure: Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines
timeFrame: Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)
Secondary outcomes:
measure: Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)
measure: Overall Survival (OS)
timeFrame: Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)
measure: Overall Response Rate (ORR)
timeFrame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Complete Response Rate (CRR)
timeFrame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Disease Control Rate (DCR)
timeFrame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Duration of Response (DOR)
timeFrame: From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)
measure: Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5
timeFrame: Baseline up to Cycle 5 (approximately 4.6 months)
measure: Percentage of Participants Experiencing Symptom Relief
timeFrame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Time to Symptom Relief
timeFrame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Time to Symptom Progression
timeFrame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
measure: Observed Plasma Concentration for Alisertib
timeFrame: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose
measure: Observed Plasma Concentration for Paclitaxel
timeFrame: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose
Other outcomes:
measure: Biomarker Correlative Studies Including Circulating Tumor Cells and Circulating DNA Assessments
timeFrame: Day 1 cycle 1 in a 28-day cycle
measure: Health Related Quality of Life (HRQOL )
timeFrame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
Locations:
city: Los Angeles
country: United States
state: California
city: Sacramento
country: United States
state: California
city: New Haven
country: United States
state: Connecticut
city: Washington
country: United States
state: District of Columbia
city: Boca Raton
country: United States
state: Florida
city: Hollywood
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Cleveland
country: United States
state: Ohio
city: Hershey
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Edegem
country: Belgium
city: Gent
country: Belgium
city: Kortrijk
country: Belgium
city: Leuven
country: Belgium
city: Mons
country: Belgium
city: Roeselare
country: Belgium
city: Edmonton
country: Canada
state: Alberta
city: Hamilton
country: Canada
state: Ontario
city: Greenfield Park
country: Canada
city: Olomouc
country: Czechia
city: Ostrava
country: Czechia
city: Praha
country: Czechia
city: Usti Nad Labem
country: Czechia
city: Grenoble
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Paris
country: France
city: Pessac
country: France
city: Rennes
country: France
city: Berlin
country: Germany
city: Frankfurt
country: Germany
city: Freiburg
country: Germany
city: Luebeck
country: Germany
city: Budapest
country: Hungary
city: Farkasgyepu
country: Hungary
city: Szolnok
country: Hungary
city: Tatabanya
country: Hungary
city: Torokbalint
country: Hungary
city: Milano
country: Italy
city: Orbassano
country: Italy
city: Parma
country: Italy
city: Gdansk
country: Poland
city: Mrozy
country: Poland
city: Warszawa
country: Poland
city: Wodzislaw Slaski
country: Poland
city: A Coruna
country: Spain
city: Barcelona
country: Spain
city: Girona
country: Spain
city: Madrid
country: Spain
city: Sevilla
country: Spain
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Owonikoko TK, Niu H, Nackaerts K, Csoszi T, Ostoros G, Mark Z, Baik C, Joy AA, Chouaid C, Jaime JC, Kolek V, Majem M, Roubec J, Santos ES, Chiang AC, Speranza G, Belani CP, Chiappori A, Patel MR, Czebe K, Byers L, Bahamon B, Li C, Sheldon-Waniga E, Kong EF, Williams M, Badola S, Shin H, Bedford L, Ecsedy JA, Bryant M, Jones S, Simmons J, Leonard EJ, Ullmann CD, Spigel DR; C14018 study investigators. Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses. J Thorac Oncol. 2020 Feb;15(2):274-287. doi: 10.1016/j.jtho.2019.10.013. Epub 2019 Oct 23.