Clinical trial NCT01602315: A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Official title: A Phase Ib Dose Escalation/Randomized Phase II, Multicenter, Open-label Study of BYL719 in Combination With Cetuximab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Recurrent Head and Neck Squamous Cell Carcinoma
Metastatic Head and Neck Squamous Cell Carcinoma
Keywords: BYL719
PI3K inhibitor
PIK3CA
cetuximab
EGFR
HNSCC
RM HNSCC
platinum-based chemotherapy
(RM HNSCC) patients
resistant or ineligible/intolerant to platinum-based chemotherapy
swallowing dysfunction
G-tube
alpelisib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-05-18
Enrollment: 179
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 was a multi-center, open-label, Phase Ib dose escalation /Phase II study in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) patients considered to be resistant, ineligible or intolerant to platinum-based chemotherapy. The Phase Ib included three arms. Three different methods of administration and two different BYL719 formulations were studied to determine the MTD and/or RP2D of BYL719 in combination with cetuximab:

Arm A - film-coated whole tablets were orally administered to patients who were able to swallow the tablets; Arm B - a drinkable suspension prepared from crushed film-coated tablets was administered orally to patients with swallowing dysfunction Arm C - a suspension from a dispersible tablet administered via G-tube, in patients with swallowing dysfunction. Arm C was used to investigate the pharmacokinetics (PK), compared to Arm A (film coated tablet), and safety of the dispersible tablet of the dispersible tablet formulation of BYL719.

The Phase II investigated the clinical efficacy of BYL719 and consisted of an open label, randomized Phase II part investigating BYL719 in combination with cetuximab compared to cetuximab alone in patients resistant or intolerant to platinum and naïve to cetuximab (Scheme 1: Arm 1 and Arm 2), and a non-randomized Phase II part Scheme 2: Arm 3. In addition, patients who experienced disease progression in Arm 2 (cetuximab) were allowed to switch to the combination regimen (cross-over, Arm 2B). The safety of the BYL719 in combination with cetuximab was also further characterized in Arms 1, 2B and 3.

Patients were treated until progression of disease), unacceptable toxicity, or withdrawal of informed consent, whichever occurred first (except for phase II Arm 2 had the opportunity to crossover to the combination treatment (Arm 2B). In the follow-up period all patients had to complete the safety follow-up assessments within 30 days after the last dose of the study treatment. Patients who did not have disease progression at the time of discontinuation of study treatment were radiologically followed for disease status until disease progression, initiation of subsequent anticancer therapies, or death, whichever occurred first. In addition, all patients enrolled in Phase II were followed for survival.


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Patients with histologically/cytologically-confirmed HNSCC
* Patients must be resistant to platinum-based chemotherapy, or be ineligible (due to medical comorbidities) or intolerant to platinum-based therapy per medical history
* For Phase Ib, there is no restriction on the number of prior therapies for recurrent or metastatic disease
* For Phase II, patients may have received a maximum of 1 prior line of therapy for recurrent or metastatic disease
* For Phase Ib, prior cetuximab or other EGFR-targeted antibody therapy is allowed regardless of the prior treatment settings.
* For Phase II, Arms 1 and 2, prior cetuximab or other EGFR-targeted antibody therapy is allowed only if administered in the induction setting, or concurrently with radiation in the curative setting, with the last dose of cetuximab administered at least 12 months prior to starting the study treatment. For Arm 3, prior cetuximab must have been administered in the curative, recurrent or metastatic disease setting and disease progression documented within 9 months of the last dose of cetuximab administered in that setting. This regimen (including both platinum and cetuximab) must be the most recent anti-neoplastic treatment regimen administered.
* Patients with swallowing dysfunction who are unable to swallow BYL719 whole tablets and are not using feeding tubes for study drug administration can participate in the Phase Ib Arm B. For the Phase II, these patients with swallowing dysfunction may participate if able to drink the suspension and results of Arm B confirm the use of this method. Patients with swallowing dysfunction requiring G tube (G/PEG tube) for study drug administration may participate in Phase II if Arm C confirms dispersible tablet via G tube administration is permitted if the administration of drinkable suspension of BYL719 is allowed to be used in Phase II.
* Availability of a representative tumor specimen. Patients enrolled in Arm 3 of Phase II must have disease sites amenable to biopsy unless prior agreement between Novartis and the Investigator.
* At least one measurable or non-measurable lesion as per RECIST 1.1 criteria for patients in Phase Ib; Measurable disease as determined by RECIST v1.1 for Phase II patients
* World Health Organization (WHO) Performance Status (PS) ≤ 2
* Adequate organ function
* Negative serum pregnancy test.

Exclusion Criteria:

* Prior treatment with PI3K-inhibitors
* Patients with a prior serious infusion reaction to cetuximab
* Patients with uncontrolled CNS tumor metastatic involvement
* Clinically significant cardiac disease or impaired cardiac function
* Patients with diabetes mellitus
* Impaired GI function or GI disease
* History of another malignancy within 2 years prior to starting study treatment
* Pregnant or nursing (lactating) women

Primary outcomes:
measure: Phase Ib Arms A: Probability That Dose Limiting Toxicities (DLTs) Rate is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days)
timeFrame: until disease progression or intolerable toxicity (approximately 6 months)
measure: Phase Ib Arm B: Probability That Distribution of Dose Limiting Toxicities (DLTs) is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days)
timeFrame: until disease progression or intolerable toxicity (approximately 6 months)
measure: For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days)
timeFrame: until disease progression or intolerable toxicity (approximately 6 months)
measure: Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review
timeFrame: approximately 6 months
measure: Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1
timeFrame: approximately 6 months
measure: Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment
timeFrame: 6 months
Secondary outcomes:
measure: Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1
timeFrame: approximately 6 months
measure: Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II: Randomized Best Overall Response as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II: Randomized Overall Survival (OS) by Treatment
timeFrame: approximately 1 year
measure: Phase II: Non-Randomized Overall Survival (OS) by Treatment
timeFrame: approximately 1 year
measure: For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1
timeFrame: approximately 6 months
measure: Phase II, Scheme 1 (Arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1
timeFrame: Approximately 6 months
measure: Phase II, Scheme 2 (Arm 2B): Overall Survival (OS) for the Cross-over
timeFrame: approximately 1 year
measure: Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment
timeFrame: 1 to 24 hours post dose (Day 1 Cycle 1)
measure: Phase Ib: Cmax for BYL719 by Treatment
timeFrame: Day 1 Cycle 1
measure: Phase Ib: Tmax for BYL719 by Treatment
timeFrame: Day 1 Cycle 1
measure: Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 After Continuous Dose Administration (Steady State)
timeFrame: Day 1 Cycle 1
measure: Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State)
timeFrame: Day 1 Cycle 1
measure: Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State)
timeFrame: Day 1 Cycle 1
measure: Phase Ib: Notable Abnormal Vital Signs by Treatment
timeFrame: approximately 6 months
measure: Phase Ib: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities
timeFrame: baseline, post baseline
measure: For Phase II: Notable Abnormal Vital Signs by Treatment
timeFrame: approximately 6 months
measure: For Phase II: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities
timeFrame: baseline, post baseline during the entire study period (approximately 1 year)
measure: Phase II: Progression Free Survival (PFS) Based on Investigator's Assessment With Treatment
timeFrame: approximately 6 months
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Jacksonville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Kuei-Shan Chiang
country: Taiwan
facility: Novartis Investigative Site
state: Taoyuan/ Taiwan ROC
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: