A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Phase 1

Terminated

Conditions: Recurrent Head and Neck Squamous Cell Carcinoma
Metastatic Head and Neck Squamous Cell Carcinoma

Interventions: Drug: BYL719 as dispersible tablets (DT)
Drug: BYL719 as film-coated (FC) whole tablets
Biological: cetuximab
Drug: BYL719 drink suspension

Registration Number: NCT01602315

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 179

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase Ib: C-BYL719 DT+cetux	BYL719 as dispersible tablets (DT)	Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube)
Phase II: Cross over	BYL719 as film-coated (FC) whole tablets	patients received BYL719 at RP2D in combination with cetuximab.
Phase Ib: A-BYL719 FC whole tab+cetux	BYL719 as film-coated (FC) whole tablets	Oral film-coated tablets without swallowing dysfunction.
Phase Ib: A-BYL719 FC whole tab+cetux	cetuximab	Oral film-coated tablets without swallowing dysfunction.
Phase II: 2-Cetuximab	cetuximab	Cetuximab in patients naive to cetuximab (phase ll)
Phase Ib: B-BYL719 FC drink sus+cetux	cetuximab	Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction.
Phase Ib: B-BYL719 FC drink sus+cetux	BYL719 drink suspension	Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction.
Phase II: 3-BYL719 + Cetuximab	BYL719 as film-coated (FC) whole tablets	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
Phase II: 3-BYL719 + Cetuximab	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
Phase II: 3-BYL719 + Cetuximab	BYL719 drink suspension	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
Phase II: 1-BYL719 + Cetuximab	BYL719 as film-coated (FC) whole tablets	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
Phase II: 1-BYL719 + Cetuximab	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
Phase II: 1-BYL719 + Cetuximab	BYL719 drink suspension	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
Phase Ib: C-BYL719 DT+cetux	cetuximab	Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube)
Phase II: Cross over	cetuximab	patients received BYL719 at RP2D in combination with cetuximab.

Primary Outcome Measures

Name	Time	Method
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)	until disease progression or intolerable toxicity (approximately 6 months)	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.
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)	until disease progression or intolerable toxicity (approximately 6 months)	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.
For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days)	until disease progression or intolerable toxicity (approximately 6 months)	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.
Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1	approximately 6 months	Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.
Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment	6 months	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)
Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review	approximately 6 months	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.

Secondary Outcome Measures

Name	Time	Method
For Phase II: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities	baseline, post baseline during the entire study period (approximately 1 year)	Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
Phase II: Progression Free Survival (PFS) Based on Investigator's Assessment With Treatment	approximately 6 months	Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
Phase II: Non-Randomized Overall Survival (OS) by Treatment	approximately 1 year	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
Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State)	Day 1 Cycle 1	Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1	approximately 6 months	Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.
Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1	approximately 6 months	Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)
Phase II: Randomized Overall Survival (OS) by Treatment	approximately 1 year	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
For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1	approximately 6 months	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
Phase II, Scheme 1 (Arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1	Approximately 6 months	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)
Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1	approximately 6 months	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
Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1	approximately 6 months	Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C.
Phase II: Randomized Best Overall Response as Per RECIST v1.1	approximately 6 months	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
Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1	approximately 6 months	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
Phase II, Scheme 2 (Arm 2B): Overall Survival (OS) for the Cross-over	approximately 1 year	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.
Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment	1 to 24 hours post dose (Day 1 Cycle 1)	Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Phase Ib: Cmax for BYL719 by Treatment	Day 1 Cycle 1	Non compartmental Cmax derived after single dose at Cycle 1 Day 1
Phase Ib: Tmax for BYL719 by Treatment	Day 1 Cycle 1	Non compartmental Cmax derived after single dose at Cycle 1 Day 1
Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State)	Day 1 Cycle 1	Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Phase Ib: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities	baseline, post baseline	Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.
For Phase II: Notable Abnormal Vital Signs by Treatment	approximately 6 months	Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 After Continuous Dose Administration (Steady State)	Day 1 Cycle 1	Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
Phase Ib: Notable Abnormal Vital Signs by Treatment	approximately 6 months	Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.