This is 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 first aim of the Phase Ib is to determine the Maximum Tolerated Dose(s) (MTD(s)) and/or the Recommended Phase II Dose(s) (RP2D(s)) for BYL719 in combination with cetuximab This part will include two different arms using two different administration methods of BYL719 tablets together with cetuximab as recommended by the label: Arm A - whole tablets will be administered to patients able to swallow the tablets vs. Arm B - a drinkable suspension prepared from crushed tablets will be administered to patients with swallowing dysfunction. The second aim of the Phase Ib is to compare the pharmacokinetics (PK) of the new dispersible tablet formulation of BYL719 in combination with cetuximab. A third arm will be opened: Arm C, which will use a suspension from a dispersible tablet administered via gastric feeding tube (G tube). The safety, tolerability, PK, PD, and efficacy will be investigated separately in the Phase Ib arms. The MTD/RP2D will only be investigated independently for Arm A and B. The one of Arm B will be compared to that of Arm A. If the MTD/RP2D is the same, then both administration methods of BYL719 may be used in Phase II. If the MTD/RP2D is different, then only the administration of BYL719 whole tablets will be allowed in the Phase II. Arm C is an independent relative bioavailability study of the new dispersible tablet formulation of BYL719, which will begin at the starting dose/RP2D identified with a safety cohort followed by an expansion cohort. There will be no dose escalation or de-escalation in this Arm. If either the safety or pharmacokinetic profile of the RP2D of 300 mg QD in Arm C is not comparable with Arm A, then enrollment in Arm C will cease and the dispersible tablet will not be implemented in Phase II.
The Phase Ib dose escalation part is expected to enroll approximately 12 patients for Arm A and B and will be guided by a Bayesian logistic regression model (BLRM). The available safety, tolerability, PK, PD and efficacy data, as well as the recommendations from the BLRM, are used to determine the dose combination for the next cohort(s). The Phase II part of the study will commence upon MTD/RP2D declaration of Arm A in Phase Ib, regardless of the progress of Arm B and C.
The Phase II part will assess the clinical efficacy of BYL719 in combination with cetuximab in two patient populations: patients will be assigned to one of two schemes of enrollment based on prior therapy with cetuximab.
Patients considered cetuximab naïve per protocol will be assigned to Scheme 1. The primary purpose of this scheme is to assess the anti-tumor activity of BYL719 in combination with cetuximab (Arm 1) vs. cetuximab as single-agent (Arm 2) in RM HNSCC patients' naïve to cetuximab. Patients in scheme 1 will be randomized in a 2:1 ratio via IRT in two Phase II arms: BYL719 in combination with cetuximab (Arm 1) vs. cetuximab as single-agent (Arm 2). Patients randomized to Arm 2 (cetuximab monotherapy) will have the opportunity to cross-over to combination treatment with BYL719 + cetuximab after experiencing disease progression. Arm 1 will consist of approximately 66 patients and Arm 2 of approximately 33 patients.
Patients having received prior cetuximab per protocol will be assigned to Scheme 2. The primary purpose of this scheme is to assess the anti-tumor activity of BYL719 in combination with cetuximab in RM HNSCC cetuximab resistant patients (Arm 3). Patients in this scheme will not be randomized. 40 patients will be enrolled. Phase II will further characterize the safety and PK of the drug combination.
Patients will be treated until progression of disease (except for phase II Arm 2), unacceptable toxicity, or withdrawal of informed consent, whichever occurs first. Patients enrolled in Arm 2 experiencing disease progression will have the opportunity to crossover to the combination treatment (Arm 2B) and they will continue until they experience unacceptable toxicity that precludes any further treatment, until disease progression, and/or until treatment is discontinued at the discretion of the Investigator or by patient refusal. In the follow-up period all patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment. Patients who have not progressed at the time of discontinuation of study treatment should be radiologically followed for disease status until disease progression, initiation of subsequent anticancer therapies, or death, whichever occurs first. In addition, all patients enrolled in Phase II will be followed for survival.