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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01602315




Registration number
NCT01602315
Ethics application status
Date submitted
16/05/2012
Date registered
18/05/2012
Date last updated
21/05/2018

Titles & IDs
Public title
A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Scientific 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
Secondary ID [1] 0 0
2011-006017-34
Secondary ID [2] 0 0
CBYL719X2104
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Head and Neck Squamous Cell Carcinoma 0 0
Metastatic Head and Neck Squamous Cell Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - BYL719 as film-coated (FC) whole tablets
Treatment: Drugs - BYL719 as dispersible tablets (DT)
Other interventions - cetuximab
Treatment: Drugs - BYL719 drink suspension

Experimental: Phase Ib: A-BYL719 FC whole tab+cetux - Oral film-coated tablets without swallowing dysfunction.

Experimental: Phase II: 2-Cetuximab - Cetuximab in patients naive to cetuximab (phase ll)

Experimental: Phase Ib: B-BYL719 FC drink sus+cetux - Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction.

Experimental: Phase II: 3-BYL719 + Cetuximab - BYL719 + cetuximab in patients resistant to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Experimental: Phase II: 1-BYL719 + Cetuximab - BYL719 + Cetuximab in Patients naive to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Experimental: Phase Ib: C-BYL719 DT+cetux - Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube)

Experimental: Phase II: Cross over - patients received BYL719 at RP2D in combination with cetuximab.


Treatment: Drugs: BYL719 as film-coated (FC) whole tablets
Oral alpha-specific PI3K inhibitor

Treatment: Drugs: BYL719 as dispersible tablets (DT)
New formulation of the oral alpha-specific PI3K inhibitor

Other interventions: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR

Treatment: Drugs: BYL719 drink suspension
Oral alpha-specific PI3K inhibitor

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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) - Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) excessive toxicity. The combination treatment was considered superior to cetuximab alone if the posterior probability (HR > 1) < 10%, and the posterior median HR < 0.7.
Timepoint [1] 0 0
until disease progression or intolerable toxicity (approximately 6 months)
Primary outcome [2] 0 0
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) - Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm B (crushed film-coated tablets as an oral suspension with swallowing dysfunction). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) excessive toxicity. The combination treatment was considered superior to cetuximab alone if the posterior probability (HR > 1) < 10%, and the posterior median HR < 0.7.
Timepoint [2] 0 0
until disease progression or intolerable toxicity (approximately 6 months)
Primary outcome [3] 0 0
For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days) - Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets) and arm B (BYL719 administered as a drinkable suspension in patients with swallowing dysfunction).
6 months is an approximate timeframe.
Timepoint [3] 0 0
until disease progression or intolerable toxicity (approximately 6 months)
Primary outcome [4] 0 0
Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review - Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab.
6 months is an approximate timeframe.
Timepoint [4] 0 0
approximately 6 months
Primary outcome [5] 0 0
Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1 - Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.
Timepoint [5] 0 0
approximately 6 months
Primary outcome [6] 0 0
Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment - Comparison of single-dose exposure of BYL719 dispersible tablet via G-tube in combination with cetuximab in RM HNSCC to that of Arm A (film-coated tables)
Timepoint [6] 0 0
6 months
Secondary outcome [1] 0 0
Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1 - Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab
Timepoint [1] 0 0
approximately 6 months
Secondary outcome [2] 0 0
Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1 - Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C.
Timepoint [2] 0 0
approximately 6 months
Secondary outcome [3] 0 0
Phase II: Randomized Best Overall Response as Per RECIST v1.1 - Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Timepoint [3] 0 0
approximately 6 months
Secondary outcome [4] 0 0
Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1 - Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Timepoint [4] 0 0
approximately 6 months
Secondary outcome [5] 0 0
Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 - Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.
Timepoint [5] 0 0
approximately 6 months
Secondary outcome [6] 0 0
Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 - Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)
Timepoint [6] 0 0
approximately 6 months
Secondary outcome [7] 0 0
Phase II: Randomized Overall Survival (OS) by Treatment - Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Timepoint [7] 0 0
approximately 1 year
Secondary outcome [8] 0 0
Phase II: Non-Randomized Overall Survival (OS) by Treatment - Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Timepoint [8] 0 0
approximately 1 year
Secondary outcome [9] 0 0
For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 - Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C
CR=complete response PR=partial response
Timepoint [9] 0 0
approximately 6 months
Secondary outcome [10] 0 0
Phase II, Scheme 1 (Arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 - Phase II: Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab.
Complete response (CR); Partial response (PR); Stable disease (SD)
Timepoint [10] 0 0
Approximately 6 months
Secondary outcome [11] 0 0
Phase II, Scheme 2 (Arm 2B): Overall Survival (OS) for the Cross-over - Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab.
Timepoint [11] 0 0
approximately 1 year
Secondary outcome [12] 0 0
Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment - Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Timepoint [12] 0 0
1 to 24 hours post dose (Day 1 Cycle 1)
Secondary outcome [13] 0 0
Phase Ib: Cmax for BYL719 by Treatment - Non compartmental Cmax derived after single dose at Cycle 1 Day 1
Timepoint [13] 0 0
Day 1 Cycle 1
Secondary outcome [14] 0 0
Phase Ib: Tmax for BYL719 by Treatment - Non compartmental Cmax derived after single dose at Cycle 1 Day 1
Timepoint [14] 0 0
Day 1 Cycle 1
Secondary outcome [15] 0 0
Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 After Continuous Dose Administration (Steady State) - Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Timepoint [15] 0 0
Day 1 Cycle 1
Secondary outcome [16] 0 0
Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State) - Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Timepoint [16] 0 0
Day 1 Cycle 1
Secondary outcome [17] 0 0
Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State) - Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Timepoint [17] 0 0
Day 1 Cycle 1
Secondary outcome [18] 0 0
Phase Ib: Notable Abnormal Vital Signs by Treatment - Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.
Timepoint [18] 0 0
approximately 6 months
Secondary outcome [19] 0 0
Phase Ib: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities - Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.
Timepoint [19] 0 0
baseline, post baseline
Secondary outcome [20] 0 0
For Phase II: Notable Abnormal Vital Signs by Treatment - Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
Timepoint [20] 0 0
approximately 6 months
Secondary outcome [21] 0 0
For Phase II: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities - Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
Timepoint [21] 0 0
baseline, post baseline during the entire study period (approximately 1 year)
Secondary outcome [22] 0 0
Phase II: Progression Free Survival (PFS) Based on Investigator's Assessment With Treatment - Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Timepoint [22] 0 0
approximately 6 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Melbourne
Recruitment hospital [2] 0 0
Novartis Investigative Site - Murdoch
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
South Carolina
Country [10] 0 0
United States of America
State/province [10] 0 0
Tennessee
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
Canada
State/province [12] 0 0
Ontario
Country [13] 0 0
France
State/province [13] 0 0
Lyon Cedex
Country [14] 0 0
France
State/province [14] 0 0
Toulouse Cedex 9
Country [15] 0 0
Hong Kong
State/province [15] 0 0
Shatin, New Territories
Country [16] 0 0
Korea, Republic of
State/province [16] 0 0
Korea
Country [17] 0 0
Korea, Republic of
State/province [17] 0 0
Seoul
Country [18] 0 0
Netherlands
State/province [18] 0 0
Maastricht
Country [19] 0 0
Netherlands
State/province [19] 0 0
Nijmegen
Country [20] 0 0
Singapore
State/province [20] 0 0
Singapore
Country [21] 0 0
Taiwan
State/province [21] 0 0
Taiwan ROC
Country [22] 0 0
Taiwan
State/province [22] 0 0
Taoyuan/ Taiwan ROC
Country [23] 0 0
Taiwan
State/province [23] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01602315
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT01602315