Study of Efficacy and Safety of Buparlisib (BKM120) Plus Paclitaxel Versus Placebo Plus Paclitaxel in Recurrent or Metastatic Head and Neck Cancer Previously Pre-treated With a Platinum Therapy

• ClinicalTrials.gov Identifier: NCT01852292
• Recruitment Status: Terminated
• First Posted: May 13, 2013
• Results First Posted: June 26, 2018
• Last Update Posted: July 24, 2018
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 8, 2013
• First Posted Date: May 13, 2013
• Results First Submitted Date: March 30, 2018
• Results First Posted Date: June 26, 2018
• Last Update Posted Date: July 24, 2018
• Actual Study Start Date: October 1, 2013
• Actual Primary Completion Date: March 30, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 24, 2018)

Progression Free Survival (PFS) Per Investigator Assessment [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]

PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression per RECIST v. 1.1 or death due to any cause. If a patient has not progressed or died at the analysis cut-off date or when the patient receives further anti-neoplastic therapy, PFS was censored on the date of the last adequate tumor assessment before the earlier of the cut-off date or start of the further anti-neoplastic therapy date.

Original Primary Outcome Measures (submitted: May 10, 2013)

Progression Free Survival (PFS) [ Time Frame: at 4 weeks after study treatment start ]

To estimate the efficacy of buparlisib in combination with paclitaxel

Current Secondary Outcome Measures (submitted: June 24, 2018)

• Overall Survival (OS) [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]
  Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last contact.
• Overall Response Rate (ORR) as Per Local Radiological Assessment [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]
  ORR: percentage of patients with best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1. CR is defined as disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm).
• Time to Response (TTR) as Per Local Radiological Assessment [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]
  TTR is the time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently) according to RECIST v1.1. CR is defined as disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm).
• Disease Control Rate (DCR) as Per Local Radiological Assessment [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]
  DCR is the percentage of patients with a best overall response of CR, PR or stable disease (SD), according to RECIST v1.1. CR is defined as disappearance of all target lesions & any pathological lymph nodes must have a short axis of <10 mm & the disappearance of all non-target lesions). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). SD is defined as neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2.
• Duration of Response (DoR) as Per Local Investigator [ Time Frame: 4 weeks and thereafter every 6 weeks until disease progression or death up to 3.5 years ]
  DoR is the time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease according to RECIST v1.1 .
• Health-related Quality of Life (HRQoL):Time to 10% Definitive Deterioration in the Global Health Status/Quality of Life Per EORTC-QLQ-C30 [ Time Frame: Baseline, every 6 weeks starting from cycle 2 day 15 up to 3.5 years ]
  A summary of EORTC-QLQ-C30 scores by time window. Time to deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive Deterioration in global health status and symptoms was defined as a decrease in the subscale score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. If a patient had not had an event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last quality of life (QoL) evaluation.
• Health-related Quality of Life (HRQoL):Time to 10% Definitive Deterioration in the Head and Neck Cancer Symptoms Scales for Pain, Speech Problems, Swallowing and Sense Problems Per EORTC-QLQ-HN35 [ Time Frame: Baseline, every 6 weeks starting from cycle 2 day 15 up to 3.5 years ]
  A summary of EORTC-QLQ-HN35 scores by time window. Time to deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive Deterioration in global health status and symptoms was defined as an increase in the subscale score of at least 10% compared to baseline, with no later decrease above this threshold observed during the course of the study. If a patient had not had an event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last quality of life (QoL) evaluation.
• Plasma Concentration-time Profiles of BKM120 Pharmacokinetics (PK) for AUC0-24 and AUClast [ Time Frame: Time point(s) at which PK samples for Non-Compartmental analysis were collected were 0, 0.5,1,1.5, 2, 3, 4, 6, 9 and 24 hours at Cycle 1, Day 15 ]
  To Characterize PK of buparlisib given in combination with paclitaxel for AUC0-24 (area under plasma concentration-time curve from time 0 to end of dosing interval of 24 hours) & AUClast (AUC from time 0 to last measurable concentration sampling time).
• Plasma Concentration-time Profiles of BKM120 Pharmacokinetics (PK) for Cmax [ Time Frame: Time point(s) at which PK samples for Non-Compartmental analysis were collected were 0, 0.5,1,1.5, 2, 3, 4, 6, 9 and 24 hours at Cycle 1, Day 15 ]
  To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for Cmax.
• Plasma Concentration-time Profiles of BKM120 Pharmacokinetics (PK) for Tmax [ Time Frame: Time point(s) at which PK samples for Non-Compartmental analysis were collected were 0, 0.5,1,1.5, 2, 3, 4, 6, 9 and 24 hours at Cycle 1, Day 15 ]
  To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for Tmax.
• Plasma Concentration-time Profiles of BKM120 Pharmacokinetics (PK) for CL/F [ Time Frame: Time point(s) at which PK samples for Non-Compartmental analysis were collected were 0, 0.5,1,1.5, 2, 3, 4, 6, 9 and 24 hours at Cycle 1, Day 15 ]
  To characterize the pharmacokinetics of buparlisib given in combination with paclitaxel for CL/F.

Original Secondary Outcome Measures (submitted: May 10, 2013)

• Overall Survival [ Time Frame: every 3 months for 2 years ]
  To assess the efficacy of the combination with paclitaxel in this patient population in terms of overall survival
• Safety and Tolerability - frequency and severity of adverse events [ Time Frame: on an ongoing basis for a maximum of 2 years. ]
  To assess the safety and tolerability of buparlisib in combination with paclitaxel in this patient population
• Overall Response Rate (ORR) [ Time Frame: at 4 weeks after study treatment start and every 6 weeks afterwards until 2 years. ]
• Time to Response (TTR) [ Time Frame: at 4 weeks after study treatment start and every 6 weeks afterwards until 2 years. ]
• Disease Control Rate (DCR) [ Time Frame: at 4 weeks after study treatment start and every 6 weeks afterwards until 2 years. ]
• Duration of Response (DoR) [ Time Frame: at 4 weeks after study treatment start and every 6 weeks afterwards until 2 years. ]
• Change from baseline in the global health status/QOL and pain scale scores of the EORTC QLQ-C30 and QLQ-HN35 [ Time Frame: baseline and every 6 weeks after randomization for 2 years . ]
  Percentage of change
• Time to definitive 10% deterioration in the global health status/QOL (quality of life) [ Time Frame: baseline, and every 6 weeks after randomization for maximum for 2 years ]
• Pain scale scores of the EORTC QLQ-C30 and QLQ-HN35 [ Time Frame: baseline, and every 6 weeks after randomization for maximum for 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Efficacy and Safety of Buparlisib (BKM120) Plus Paclitaxel Versus Placebo Plus Paclitaxel in Recurrent or Metastatic Head and Neck Cancer Previously Pre-treated With a Platinum Therapy
• Official Title: Double Blind, Placebo Controlled Study Assessing the Efficacy of Buparlisib (BKM120) Plus Paclitaxel Versus Placebo Plus Paclitaxel in Patients With Platinum Pre-treated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)
• Brief Summary: Phase II Study of efficacy and safety of buparlisib (BKM120) plus paclitaxel versus placebo plus paclitaxel in recurrent or metastatic Head and Neck cancer previously pre-treated with a platinum therapy.The primary endpoint was PFS and the key secondary endpoint was Overall Survival.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Head and Neck Squamous Cell Carcinoma

Intervention

• Drug: Buparlisib
  Buparlisib comes in gelatin capsules and is taken orally at a dose of 100 mg/day.
  Other Name: BKM120
• Drug: Buparlisib matching Placebo
  Buparlisib matching placebo comes in gelatin capsules and is taken orally at a dose of 100 mg/day.
• Drug: Paclitaxel
  Paclitaxel is an intravenous infusion that is given once every week in 80 mg/m^2.

Study Arms

• Experimental: Buparlisib + weekly Paclitaxel
  Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m^2 weekly.
  Interventions:

  • Drug: Buparlisib
  • Drug: Paclitaxel
• Placebo Comparator: Buparlisib matching placebo + Paclitaxel
  Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m^2 weekly.
  Interventions:

  • Drug: Buparlisib matching Placebo
  • Drug: Paclitaxel

• Publications *: Soulieres D, Faivre S, Mesia R, Remenar E, Li SH, Karpenko A, Dechaphunkul A, Ochsenreither S, Kiss LA, Lin JC, Nagarkar R, Tamas L, Kim SB, Erfan J, Alyasova A, Kasper S, Barone C, Turri S, Chakravartty A, Chol M, Aimone P, Hirawat S, Licitra L. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017 Mar;18(3):323-335. doi: 10.1016/S1470-2045(17)30064-5. Epub 2017 Jan 26.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 26, 2018): 157
• Original Estimated Enrollment (submitted: May 10, 2013): 150
• Actual Study Completion Date: March 30, 2017
• Actual Primary Completion Date: March 30, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patient has histologically/cytologically-confirmed HNSCC.
• Patient has archival or fresh tumor tissue for the analysis of PI3K-related biomarkers. One tumor block (preferred) or a minimum of 12 unstained slides to be provided. Enrollment in the study is contingent on confirmation of an adequate amount of tumor tissue.
• Patients with recurrent or metastatic disease resistant to platinum-based chemotherapy (defined as progression while on platinum-based chemotherapy given in the recurrent/metastatic setting). Pretreatment with cetuximab is allowed
• Measurable disease as determined by per RECIST criteria v1.1. If the only site of measurable disease is a previously irradiated lesion, documented progression of disease and a 4 week period since radiotherapy completion is required
• Adequate bone marrow function and organ function
• ECOG Performance Status ≤ 1

Exclusion Criteria:

• Patient has received previous treatment with any AKT, mTOR inhibitors or PI3K pathway inhibitors;
• Patient treated with more than one prior chemotherapy regimen for recurrent/metastatic disease
• Patient has symptomatic CNS metastases. Patients with asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior local treatment for CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery) and must have stable low dose of corticosteroid therapy;
• Patient has not recovered to ≤ grade 1 (except alopecia) from related side effects of any prior antineoplastic therapy
• Patient has any of the following cardiac abnormalities:symptomatic congestive heart failure, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); myocardial infarction ≤ 6 months prior to enrolment, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, symptomatic pericarditis, QTcF > 480 msec on the screening ECG (using the QTcF formula);

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Hungary, India, Ireland, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Switzerland, Taiwan, Thailand, United Kingdom, United States

Administrative Information

• NCT Number: NCT01852292
• Other Study ID Numbers: CBKM120H2201; 2013-000744-26 ( EudraCT Number )
• 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

• Plan to Share IPD: Undecided

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: June 2018