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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01602315
Recruitment Status : Terminated (early termination due to Sponsor decision (slow recruitment))
First Posted : May 18, 2012
Results First Posted : May 21, 2018
Last Update Posted : December 29, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.


Condition or disease Intervention/treatment Phase
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) Biological: cetuximab Drug: BYL719 drink suspension Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 179 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : November 12, 2012
Actual Primary Completion Date : September 16, 2016
Actual Study Completion Date : September 16, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Cetuximab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase Ib: A-BYL719 FC whole tab+cetux
Oral film-coated tablets without swallowing dysfunction.
 Drug: BYL719 as film-coated (FC) whole tablets
Oral alpha-specific PI3K inhibitor
Other Names:
  • NVP-BYL719
  • alpelisib

Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux
Experimental: Phase II: 2-Cetuximab
Cetuximab in patients naive to cetuximab (phase ll)
 Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux
Experimental: Phase Ib: B-BYL719 FC drink sus+cetux
Crushed film-coated (FC) tablets as an oral suspension with swallowing dysfunction.
 Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux

Drug: BYL719 drink suspension
Oral alpha-specific PI3K inhibitor
Other Name: NVP-BYL719
Experimental: Phase II: 3-BYL719 + Cetuximab
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
Oral alpha-specific PI3K inhibitor
Other Names:
  • NVP-BYL719
  • alpelisib

Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux

Drug: BYL719 drink suspension
Oral alpha-specific PI3K inhibitor
Other Name: NVP-BYL719
Experimental: Phase II: 1-BYL719 + Cetuximab
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
Oral alpha-specific PI3K inhibitor
Other Names:
  • NVP-BYL719
  • alpelisib

Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux

Drug: BYL719 drink suspension
Oral alpha-specific PI3K inhibitor
Other Name: NVP-BYL719
Experimental: Phase Ib: C-BYL719 DT+cetux
Dispersible tablet with swallowing dysfunction administered via a gastrostomy tube (G-tube)
 Drug: BYL719 as dispersible tablets (DT)
New formulation of the oral alpha-specific PI3K inhibitor
Other Name: NVP-BYL719

Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux
Experimental: Phase II: Cross over
patients received BYL719 at RP2D in combination with cetuximab.
 Drug: BYL719 as film-coated (FC) whole tablets
Oral alpha-specific PI3K inhibitor
Other Names:
  • NVP-BYL719
  • alpelisib

Biological: cetuximab
Recombinant chimeric monoclonal antibody driven against EGFR
Other Name: erbitux


Outcome Measures
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Primary Outcome Measures :
  1. 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) [ Time Frame: until disease progression or intolerable toxicity (approximately 6 months) ]
    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.

  2. 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) [ Time Frame: until disease progression or intolerable toxicity (approximately 6 months) ]
    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.

  3. For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 Days) [ Time Frame: until disease progression or intolerable toxicity (approximately 6 months) ]

    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.


  4. Phase II Arms 1 and 2: Progression Free Survival (PFS) as Per RECIST v1.1 by Central Radiology Review [ Time Frame: approximately 6 months ]

    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.


  5. Phase II Arm 3: Progression Free Survival (PFS) as Per RECIST V1.1 [ Time Frame: approximately 6 months ]
    Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.

  6. Phase Ib: Area Under Curve (AUC) 0-24 for BYL719 by Treatment [ Time Frame: 6 months ]
    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)


Secondary Outcome Measures :
  1. Phase II: Progression Free Survival (PFS) as Per RECIST v 1.1 [ Time Frame: approximately 6 months ]
    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

  2. Phase Ib: Progression Free Survival (PFS) as Per RECIST v1.1 [ Time Frame: approximately 6 months ]
    Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C.

  3. Phase II: Randomized Best Overall Response as Per RECIST v1.1 [ Time Frame: approximately 6 months ]
    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

  4. Phase II: Non-Randomized Best Overall Response as Per RECIST v1.1 [ Time Frame: approximately 6 months ]
    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

  5. Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 [ Time Frame: approximately 6 months ]
    Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.

  6. Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 [ Time Frame: approximately 6 months ]
    Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)

  7. Phase II: Randomized Overall Survival (OS) by Treatment [ Time Frame: approximately 1 year ]
    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

  8. Phase II: Non-Randomized Overall Survival (OS) by Treatment [ Time Frame: approximately 1 year ]
    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

  9. For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 [ Time Frame: approximately 6 months ]

    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


  10. Phase II, Scheme 1 (Arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as Per RECIST v1.1 [ Time Frame: Approximately 6 months ]

    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)


  11. Phase II, Scheme 2 (Arm 2B): Overall Survival (OS) for the Cross-over [ Time Frame: approximately 1 year ]
    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.

  12. Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment [ Time Frame: 1 to 24 hours post dose (Day 1 Cycle 1) ]
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

  13. Phase Ib: Cmax for BYL719 by Treatment [ Time Frame: Day 1 Cycle 1 ]
    Non compartmental Cmax derived after single dose at Cycle 1 Day 1

  14. Phase Ib: Tmax for BYL719 by Treatment [ Time Frame: Day 1 Cycle 1 ]
    Non compartmental Cmax derived after single dose at Cycle 1 Day 1

  15. Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 After Continuous Dose Administration (Steady State) [ Time Frame: Day 1 Cycle 1 ]
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

  16. Phase Ib: Cmax for BYL719 After Continuous Dose Administration (Steady State) [ Time Frame: Day 1 Cycle 1 ]
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

  17. Phase Ib: Tmax for BYL719 After Continuous Dose Administration (Steady State) [ Time Frame: Day 1 Cycle 1 ]
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1

  18. Phase Ib: Notable Abnormal Vital Signs by Treatment [ Time Frame: approximately 6 months ]
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.

  19. Phase Ib: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities [ Time Frame: baseline, post baseline ]
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.

  20. For Phase II: Notable Abnormal Vital Signs by Treatment [ Time Frame: approximately 6 months ]
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.

  21. For Phase II: Number of Patients With Notable Electrocardiogram (ECG) Abnormalities [ Time Frame: baseline, post baseline during the entire study period (approximately 1 year) ]
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.

  22. Phase II: Progression Free Survival (PFS) Based on Investigator's Assessment With Treatment [ Time Frame: approximately 6 months ]
    Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01602315


Locations
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United States, California
Novartis Investigative Site
Sacramento, California, United States, 95817
Novartis Investigative Site
San Francisco, California, United States, 94101
United States, Colorado
Novartis Investigative Site
Aurora, Colorado, United States, 80045
United States, Florida
Novartis Investigative Site
Jacksonville, Florida, United States, 32224
Novartis Investigative Site
Orlando, Florida, United States, 32806
United States, Georgia
Novartis Investigative Site
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Novartis Investigative Site
Boston, Massachusetts, United States, 02114
United States, Missouri
Novartis Investigative Site
Saint Louis, Missouri, United States, 63110
United States, New York
Novartis Investigative Site
New York, New York, United States, 10017
Novartis Investigative Site
New York, New York, United States, 10029
United States, Pennsylvania
Novartis Investigative Site
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Novartis Investigative Site
Charleston, South Carolina, United States, 29425
United States, Tennessee
Novartis Investigative Site
Nashville, Tennessee, United States, 37232
United States, Texas
Novartis Investigative Site
Houston, Texas, United States, 77030
Australia, Victoria
Novartis Investigative Site
Melbourne, Victoria, Australia, 3000
Australia, Western Australia
Novartis Investigative Site
Murdoch, Western Australia, Australia, 6150
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 2M9
France
Novartis Investigative Site
Lyon Cedex, France, 69373
Novartis Investigative Site
Toulouse Cedex 9, France, 31059
Hong Kong
Novartis Investigative Site
Shatin, New Territories, Hong Kong
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Korea, Republic of, 03080
Novartis Investigative Site
Seoul, Korea, Korea, Republic of, 06351
Novartis Investigative Site
Seoul, Korea, Republic of, 03722
Netherlands
Novartis Investigative Site
Maastricht, Netherlands, 5800
Novartis Investigative Site
Nijmegen, Netherlands, 6500 HB
Singapore
Novartis Investigative Site
Singapore, Singapore, 169610
Taiwan
Novartis Investigative Site
Tainan, Taiwan ROC, Taiwan, 70421
Novartis Investigative Site
Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, Taiwan, 33305
Novartis Investigative Site
Taipei, Taiwan, 10048
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Additional Information:

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01602315    
Other Study ID Numbers: CBYL719X2104
2011-006017-34 ( EudraCT Number )
First Posted: May 18, 2012    Key Record Dates
Results First Posted: May 21, 2018
Last Update Posted: December 29, 2020
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Recurrence
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
 Pathologic Processes
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Cetuximab
Antineoplastic Agents, Immunological
Antineoplastic Agents