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

Purpose

This is a multi-center, open-label, Phase Ib dose escalation / randomized Phase II study. The aim of the Phase Ib part 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. The Phase II part will assess the clinical efficacy of BYL719 in combination with cetuximab vs. cetuximab as single-agent and will further characterize the safety of the drugs combination.

The phase Ib will include two different arms using two different methods of administration 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 part.

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. All patients will be randomized in a 2:1 ratio via IRT in two Phase II arms: BYL719 in combination with cetuximab consisting of approximately 66 patients vs. cetuximab as single-agent consisting of approximately 33 patients.

Both Phase Ib and Phase II will be conducted in patients who are resistant, ineligible or intolerant to platinum-based chemotherapy.

Patients will be treated until progression of disease, unacceptable toxicity, or withdrawal of informed consent, whichever occurs first. At minimum, 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. Furthermore, all patients enrolled in Phase II will be followed for survival.

Condition	Intervention	Phase
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+cetuximab Biological: cetuximab	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Cetuximab

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (Cycle 1=28 days) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
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)
For Phase II: Progression Free Survival (PFS) as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients

Secondary Outcome Measures:

For Phase Ib: Number of patients with Adverse Events (AEs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: Plasma concentration vs. time profiles, plasma pharmacokinetics (PK) parameters of BYL719 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Determination of the single and multiple dose PK profile of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: Overall Response Rate (ORR) as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: Disease Control Rate (DCR) as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: PFS as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A and arm B
For Phase II: ORR as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients
For Phase II: DCR as per RECIST v1.1 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients
For Phase II: Overall Survival (OS) [ Time Frame: approximately 1 year ] [ Designated as safety issue: No ]
Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients
For Phase II: OS rate at 6 months (OS6) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients
For Phase Ib: Dose interruptions, reductions and dose intensity [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: Number of patients with Serious AEs (SAEs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A and arm B
For Phase Ib: Changes in laboratory values (hematology and chemistry values), vital signs, electrocardiograms (ECGs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A and arm B
For Phase II: Dose interruptions, reductions and dose intensity [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab
For Phase II: Number of patients with Adverse Events (AEs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab
For Phase II: Plasma concentration vs. time profiles, plasma pharmacokinetics (PK) parameters of BYL719 [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
Determination of the single and multiple dose PK profile of BYL719 in combination with cetuximab
For Phase II: Changes in laboratory values (hematology and chemistry values), vital signs, electrocardiograms (ECGs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab
For Phase II: Number of patients with Serious AEs (SAEs) [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
Characterization of the safety and tolerability of BYL719 in combination with cetuximab

Estimated Enrollment:	111
Study Start Date:	November 2012
Estimated Study Completion Date:	February 2015
Estimated Primary Completion Date:	January 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm A:BYL719 whole tab+cetux (phase lb)	Drug: BYL719+cetuximab Oral alpha-specific PI3K inhibitor in combination with a recombinant chimeric monoclonal antibody driven against EGFR Other Name: NVP-BYL719+erbitux
Experimental: BYL719+cetuximab (phase ll)	Drug: BYL719+cetuximab Oral alpha-specific PI3K inhibitor in combination with a recombinant chimeric monoclonal antibody driven against EGFR Other Name: NVP-BYL719+erbitux
Active Comparator: cetuximab (phase II)	Biological: cetuximab Recombinant chimeric monoclonal antibody driven against EGFR Other Name: erbitux
Experimental: Arm B: BYL719 drink sus+cetux (phase Ib)	Drug: BYL719+cetuximab Oral alpha-specific PI3K inhibitor in combination with a recombinant chimeric monoclonal antibody driven against EGFR Other Name: NVP-BYL719+erbitux

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 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, 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
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
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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01602315

Contacts

Contact: Novartis Pharmaceuticals	1-888-669-6682
Contact: Novartis Pharmaceuticals

Show 26 Study Locations

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01602315 History of Changes
Other Study ID Numbers:	CBYL719X2104, 2011-006017-34
Study First Received:	May 16, 2012
Last Updated:	April 5, 2013
Health Authority:	Australia: Therapeutic Goods Administration (TGA) Canada: Health Canada France: French National Authority for Health Hong Kong: Department of Health Korea: Korea Food and Drug Administration (KFDA) Netherlands: Dutch Healthcare Authority (Nza) Singapore: Health Sciences Authority (HSA) Taiwan: Taiwan Food and Drug Administration (TFDA) United States: Food and Drug Administration

Keywords provided by Novartis:

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

Additional relevant MeSH terms:

Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms

Neoplasms, Squamous Cell
Neoplasms by Site
Cetuximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 17, 2013