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

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