Novartis Pharmaceuticals, Novartis Pharmaceuticals
A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (RM HNSCC) Patients Who Are Resistant or Ineligible/Intolerant to Platinum-based Chemotherapy.
Recurrent Head and Neck Squamous Cell Carcinoma
Metastatic Head and Neck Squamous Cell Carcinoma
Drug: BYL719 as film-coated (FC) whole tablets
Drug: BYL719 as dispersible tablets (DT)
Drug: BYL719 as film-coated (FC) drink suspension
Phase 1/Phase 2
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
Ages Eligible: 18 Years
Accepts Healthy Volunteers:
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
World Health Organization (WHO) Performance Status (PS) ≤ 2
Adequate organ function
Negative serum pregnancy test.
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 Other protocol-defined inclusion/exclusion
criteria may apply
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Information obtained from ClinicalTrials.gov, on
8/2/2015. For additional information about
this and other clinical trials,
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