Clinical Trial Details

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Study ID CBYL719X2104
Investigator
Novartis Pharmaceuticals,   Novartis Pharmaceuticals
Title A Phase Ib/II Study of BYL719 and Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Conditions 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
Interventions Drug: BYL719+cetuximab
Drug: BYL719+cetuximab
Biological: cetuximab
Phase Phase 1/Phase 2
Purpose This is a multi-center, open-label, Phase Ib dose escalation / Phase II study. The 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 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 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 safety, tolerability, PK, PD, efficacy and MTD/RP2D will be investigated separately in the two arms and the MTD/RP2D 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. The Phase Ib dose escalation part is expected to enroll approximately 12 patients in each arm 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. 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 will either be cetuximab naïve or may have received cetuximab (or another EGFR targeted antibody) 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. Patients in scheme 1 (Arms 1 and 2) 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 with single agent cetuximab. Arm 1 will consist of approximately 66 patients and Arm 2 of approximately 33 patients. Patients having received prior cetuximab 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. Forty 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 upon treatment with single agent cetuximab will have the opportunity to crossover to the combination treatment of BYL719 and cetuximab (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.
Eligibility Ages Eligible: 18 Years
Genders Eligible:  Both
Accepts Healthy Volunteers:  No
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 that are not using feeding tubes can participate in the Phase Ib arm B. For the Phase II, these patients may participate 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 Other protocol-defined inclusion/exclusion criteria may apply
Study Location
University of California San Francisco UCSF 3
San Francisco, California, 94101
Contact Novartis Pharmaceuticals
1-888-669-6682
Information objtained from ClinicalTrials.gov, on 7/22/2014. For additional information about this and other clinical trials, visit http://clinicaltrials.gov.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01602315


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