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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: BYL719 as film-coated (FC) whole tablets
* Drug: BYL719 as dispersible tablets (DT)
* Biological: cetuximab
* Drug: BYL719 drink suspension


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: A-BYL719 FC whole tab+cetux<br>Oral film-coated tablets without swallowing dysfunction. | Drug: BYL719 as film-coated (FC) whole tablets<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: alpelisib;Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;|
| Experimental: Phase II: 2-Cetuximab<br>Cetuximab in patients naive to cetuximab (phase ll) | Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;|
| Experimental: Phase Ib: B-BYL719 FC drink sus+cetux<br>Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction. | Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;Drug: BYL719 drink suspension<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: NVP-BYL719;|
| Experimental: Phase II: 3-BYL719 + Cetuximab<br>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 | Drug: BYL719 as film-coated (FC) whole tablets<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: alpelisib;Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;Drug: BYL719 drink suspension<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: NVP-BYL719;|
| Experimental: Phase II: 1-BYL719 + Cetuximab<br>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 | Drug: BYL719 as film-coated (FC) whole tablets<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: alpelisib;Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;Drug: BYL719 drink suspension<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: NVP-BYL719;|
| Experimental: Phase Ib: C-BYL719 DT+cetux<br>Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube) | Drug: BYL719 as dispersible tablets (DT)<br>* New formulation of the oral alpha-specific PI3K inhibitor<br>* Other names: NVP-BYL719;Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;|
| Experimental: Phase II: Cross over<br>patients received BYL719 at RP2D in combination with cetuximab. | Drug: BYL719 as film-coated (FC) whole tablets<br>* Oral alpha-specific PI3K inhibitor<br>* Other names: alpelisib;Biological: cetuximab<br>* Recombinant chimeric monoclonal antibody driven against EGFR<br>* Other names: erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | until disease progression or intolerable toxicity (approximately 6 months) | 
| 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. | until disease progression or intolerable toxicity (approximately 6 months) | 
| 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. | until disease progression or intolerable toxicity (approximately 6 months) | 
| 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. | approximately 6 months | 
| 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. | approximately 6 months | 
| 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) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | approximately 6 months | 
| 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. | approximately 6 months | 
| 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 | approximately 6 months | 
| 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 | approximately 6 months | 
| 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. | approximately 6 months | 
| 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) | approximately 6 months | 
| 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 | approximately 1 year | 
| 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 | approximately 1 year | 
| 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 | approximately 6 months | 
| 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) | Approximately 6 months | 
| 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. | approximately 1 year | 
| Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment | Non compartmental PK parameters derived after single dose at Cycle 1 Day 1 | 1 to 24 hours post dose (Day 1 Cycle 1) | 
| Phase Ib: Cmax for BYL719 by Treatment | Non compartmental Cmax derived after single dose at Cycle 1 Day 1 | Day 1 Cycle 1 | 
| Phase Ib: Tmax for BYL719 by Treatment | Non compartmental Cmax derived after single dose at Cycle 1 Day 1 | Day 1 Cycle 1 | 
| 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 | Day 1 Cycle 1 | 
| Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State) | Non compartmental PK parameters derived after single dose at Cycle 1 Day 1 | Day 1 Cycle 1 | 
| Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State) | Non compartmental PK parameters derived after single dose at Cycle 1 Day 1 | Day 1 Cycle 1 | 
| 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. | approximately 6 months | 
| 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. | baseline, post baseline | 
| 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. | approximately 6 months | 
| 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. | baseline, post baseline during the entire study period (approximately 1 year) | 
| 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 | approximately 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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