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

NCT01602315 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CBYL719X21042011-006017-34
• Study Type: interventional
• Target: 179
• Locations: 9 countries
• Sites: 29

Brief Summary

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.

Conditions

Recurrent Head and Neck Squamous Cell Carcinoma; Metastatic Head and Neck Squamous Cell Carcinoma

Keywords

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; G-tube; alpelisib

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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.

  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.

  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.

  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)

  6 months

Secondary Outcomes (22)

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

  approximately 6 months

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

  approximately 6 months

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

  approximately 6 months

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

  approximately 6 months

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

  approximately 6 months

Study Arms (7)

Phase Ib: A-BYL719 FC whole tab+cetux

EXPERIMENTAL

Oral film-coated tablets without swallowing dysfunction.

Drug: BYL719 as film-coated (FC) whole tablets; Biological: cetuximab

Phase II: 2-Cetuximab

EXPERIMENTAL

Cetuximab in patients naive to cetuximab (phase ll)

Biological: cetuximab

Phase Ib: B-BYL719 FC drink sus+cetux

EXPERIMENTAL

Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction.

Biological: cetuximab; Drug: BYL719 drink suspension

Phase II: 3-BYL719 + Cetuximab

EXPERIMENTAL

BYL719 + cetuximab in patients resistant to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Drug: BYL719 as film-coated (FC) whole tablets; Biological: cetuximab; Drug: BYL719 drink suspension

Phase II: 1-BYL719 + Cetuximab

EXPERIMENTAL

BYL719 + Cetuximab in Patients naive to cetuximab. BYL719 can be administered as FC whole/crushed only or DT via G-tube in addition, depending on the Phase Ib results

Drug: BYL719 as film-coated (FC) whole tablets; Biological: cetuximab; Drug: BYL719 drink suspension

Phase Ib: C-BYL719 DT+cetux

EXPERIMENTAL

Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube)

Drug: BYL719 as dispersible tablets (DT); Biological: cetuximab

Phase II: Cross over

EXPERIMENTAL

patients received BYL719 at RP2D in combination with cetuximab.

Drug: BYL719 as film-coated (FC) whole tablets; Biological: cetuximab

Interventions

BYL719 as film-coated (FC) whole tablets DRUG

Oral alpha-specific PI3K inhibitor

Also known as: NVP-BYL719, alpelisib

Phase II: 1-BYL719 + Cetuximab; Phase II: 3-BYL719 + Cetuximab; Phase II: Cross over; Phase Ib: A-BYL719 FC whole tab+cetux

BYL719 as dispersible tablets (DT) DRUG

New formulation of the oral alpha-specific PI3K inhibitor

Also known as: NVP-BYL719

Phase Ib: C-BYL719 DT+cetux

cetuximab BIOLOGICAL

Recombinant chimeric monoclonal antibody driven against EGFR

Also known as: erbitux

Phase II: 1-BYL719 + Cetuximab; Phase II: 2-Cetuximab; Phase II: 3-BYL719 + Cetuximab; Phase II: Cross over; Phase Ib: A-BYL719 FC whole tab+cetux; Phase Ib: B-BYL719 FC drink sus+cetux; Phase Ib: C-BYL719 DT+cetux

BYL719 drink suspension DRUG

Oral alpha-specific PI3K inhibitor

Also known as: NVP-BYL719

Phase II: 1-BYL719 + Cetuximab; Phase II: 3-BYL719 + Cetuximab; Phase Ib: B-BYL719 FC drink sus+cetux

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (29)

Novartis Investigative Site

Sacramento, California, 95817, United States

Location

Novartis Investigative Site

San Francisco, California, 94101, United States

Location

Novartis Investigative Site

Aurora, Colorado, 80045, United States

Location

Novartis Investigative Site

Jacksonville, Florida, 32224, United States

Location

Novartis Investigative Site

Orlando, Florida, 32806, United States

Location

Novartis Investigative Site

Atlanta, Georgia, 30322, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

St Louis, Missouri, 63110, United States

Location

Novartis Investigative Site

New York, New York, 10017, United States

Location

Novartis Investigative Site

New York, New York, 10029, United States

Location

Novartis Investigative Site

Philadelphia, Pennsylvania, 19104, United States

Location

Novartis Investigative Site

Charleston, South Carolina, 29425, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37232, United States

Location

Novartis Investigative Site

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Murdoch, Western Australia, 6150, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Shatin, New Territories, Hong Kong, Hong Kong

Location

Novartis Investigative Site

Maastricht, 5800, Netherlands

Location

Novartis Investigative Site

Nijmegen, 6500 HB, Netherlands

Location

Novartis Investigative Site

Singapore, 169610, Singapore

Location

Novartis Investigative Site

Seoul, Korea, 03080, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 06351, South Korea

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Tainan, Taiwan ROC, 70421, Taiwan

Location

Novartis Investigative Site

Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, 33305, Taiwan

Location

Novartis Investigative Site

Taipei, 10048, Taiwan

Location

Related Publications (1)

• Razak ARA, Wang HM, Chang JY, Ahn MJ, Munster P, Blumenschein G Jr, Solomon B, Lim DW, Hong RL, Pfister D, Saba NF, Lee SH, van Herpen C, Quadt C, Bootle D, Blumenstein L, Demanse D, Delord JP. A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Target Oncol. 2023 Nov;18(6):853-868. doi: 10.1007/s11523-023-00997-z. Epub 2023 Oct 25.

  PMID: 37875771 DERIVED

Related Links

• Results for CBYL719X2104 can be found on the Novartis Clinical Trial Results Website

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Hereditary Sensory and Autonomic Neuropathies

Interventions

Alpelisib; Cetuximab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Recruitment of new patients who were resistant to both platinum \& cetuximab into Arm 3 was halted due to slow enrollment. The study was terminated early and health authorities were informed.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2012
• First Posted: May 18, 2012
• Study Start: November 12, 2012
• Primary Completion: September 16, 2016
• Study Completion: September 16, 2016
• Last Updated: December 29, 2020
• Results First Posted: May 21, 2018

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); HK (1); NL (2); TW (3); US (14); KR (3); CA (1); FR (2); SG (1)