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

Phase 2TerminatedNCT01602315

Novartis Pharmaceuticals179 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Interventions

BYL719 as film-coated (FC) whole tabletsDRUG

Oral alpha-specific PI3K inhibitor

BYL719 as dispersible tablets (DT)DRUG

New formulation of the oral alpha-specific PI3K inhibitor

cetuximabBIOLOGICAL

Recombinant chimeric monoclonal antibody driven against EGFR

BYL719 drink suspensionDRUG

Oral alpha-specific PI3K inhibitor

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (29)

Novartis Investigative Site

Sacramento, California, United States

Novartis Investigative Site

San Francisco, California, United States

Novartis Investigative Site

Aurora, Colorado, United States

Novartis Investigative Site

Jacksonville, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Outcomes

Primary Outcomes

Phase Ib Arms A: Probability That Dose Limiting Toxicities (DLTs) Rate is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days)

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). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) excessive toxicity. The combination treatment was considered superior to cetuximab alone if the posterior probability (HR \> 1) \< 10%, and the posterior median HR \< 0.7.

Time frame: until disease progression or intolerable toxicity (approximately 6 months)

Phase Ib Arm B: Probability That Distribution of Dose Limiting Toxicities (DLTs) is in the Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 Days)

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 B (crushed film-coated tablets as an oral suspension with swallowing dysfunction). Dose recommendation was based on posterior summaries including the mean, median, standard deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose combination lies in one of the following categories: (0%, 16%) under-dosing; (16%, 35%) targeted toxicity; (35%, 100%) excessive toxicity. The combination treatment was considered superior to cetuximab alone if the posterior probability (HR \> 1) \< 10%, and the posterior median HR \< 0.7.

Time frame: until disease progression or intolerable toxicity (approximately 6 months)

For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days)

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). 6 months is an approximate timeframe.

Time frame: until disease progression or intolerable toxicity (approximately 6 months)

Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review

Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab. 6 months is an approximate timeframe.

Time frame: approximately 6 months

Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1

Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.

Time frame: approximately 6 months

Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment

Comparison of single-dose exposure of BYL719 dispersible tablet via G-tube in combination with cetuximab in RM HNSCC to that of Arm A (film-coated tables)

Time frame: 6 months

Secondary Outcomes

Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1

Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab

Time frame: approximately 6 months

Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1

Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C.

Time frame: approximately 6 months

Phase II: Randomized Best Overall Response as Per RECIST v1.1

Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Time frame: approximately 6 months

Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1

Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Time frame: approximately 6 months

Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1

Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.

Time frame: approximately 6 months

Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1

Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)

Time frame: approximately 6 months

Phase II: Randomized Overall Survival (OS) by Treatment

Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Data from ClinicalTrials.gov

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Novartis Investigative Site

Atlanta, Georgia, United States

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

St Louis, Missouri, United States

Novartis Investigative Site

New York, New York, United States

Novartis Investigative Site

New York, New York, United States

...and 19 more locations

Time frame: approximately 1 year

Phase II: Non-Randomized Overall Survival (OS) by Treatment

Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Time frame: approximately 1 year

For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1

Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C CR=complete response PR=partial response

Time frame: approximately 6 months

Phase II, Scheme 1 (Arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1

Phase II: Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab. Complete response (CR); Partial response (PR); Stable disease (SD)

Time frame: Approximately 6 months

Phase II, Scheme 2 (Arm 2B): Overall Survival (OS) for the Cross-over

Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab.

Time frame: approximately 1 year

Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment

Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

Time frame: 1 to 24 hours post dose (Day 1 Cycle 1)

Phase Ib: Cmax for BYL719 by Treatment

Non compartmental Cmax derived after single dose at Cycle 1 Day 1

Time frame: Day 1 Cycle 1

Phase Ib: Tmax for BYL719 by Treatment

Non compartmental Cmax derived after single dose at Cycle 1 Day 1

Time frame: Day 1 Cycle 1

Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 After Continuous Dose Administration (Steady State)

Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

Time frame: Day 1 Cycle 1

Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State)

Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

Time frame: Day 1 Cycle 1

Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State)

Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

Time frame: Day 1 Cycle 1

Phase Ib: Notable Abnormal Vital Signs by Treatment

Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.

Time frame: approximately 6 months

Phase Ib: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities

Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.

Time frame: baseline, post baseline

For Phase II: Notable Abnormal Vital Signs by Treatment

Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.

Time frame: approximately 6 months

For Phase II: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities

Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.

Time frame: baseline, post baseline during the entire study period (approximately 1 year)

Phase II: Progression Free Survival (PFS) Based on Investigator's Assessment With Treatment

Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab

Time frame: approximately 6 months

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

Overview

Conditions

Interventions

Eligibility

Locations (29)

Outcomes

Primary Outcomes

Secondary Outcomes