Primary objective: Phase Ib: To estimate the MTD and/or RP2D of BYL719 in combination with cetuximab. Phase II: To compare the efficacy of BYL719 plus cetuximab in comparison with cetuximab monotherapy.Secondary objective (major): safety and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of DLTs (phase Ib), progression free survival (phase II).
PROTOCOL AMENDEMENT 5
Phase Ib Arm-C: AUCO-24
Secondary outcome
Adverse events, dose interruptions, reductions, dose density, PK (phase IB),
overall response rate, disease control rate, overall survival, overall survival
rate at month 6.
PROTOCOL AMENDMENT 5
Plasma concentration vs. time profiles, plasma PK parameters of BYL719 in Arm C
Background summary
EGFR (epidermal growth factor receptor) is overexpressed in around 90% of the
HNSCC (head and neck squamous cell carcinoma) and is therefore a therapeutic
target for cancer treatment. However, many patients are refractory to anti-EGFR
treatment, due to mechanisms of resistance. An established finding in the
tumors refractory to EGFR inhibition is the activation of the PI3K/AKT/mTOR
pathway leading to enhanced cell survival. Combination therapy with cetuximab
and a PI3K inhibitor could potentially help overcome this resistance. In
preclinical models, the combination of the alpha-specific PI3K inhibitor BYL719
with cetuximab demonstrated significant antitumor efficacy and strong synergy
in HNSCC cell lines in vitro and in tumor xenografts in vivo.
In clinical trials, preliminary data on tolerability and first signs of
efficacy in colorectal cancer and HNSCC patients treated with cetuximab in
combination with a PI3K inhibitor PX-866 have been reported. This study
suggests that inhibition of the PI3K pathway combined with a block of EGFR may
be used safely in patients and could lead to increased clinical efficacy.
In summary, these results provide a strong rationale for the combination
therapy of cetuximab and BYL719 in cancers where the EGFR/PI3K/AKT pathway is
activated. Both the Phase Ib and Phase II parts of the study will be conducted
in adult patients with RM HNSCC who are resistant or ineligible or intolerant
to platinum-containing chemotherapy.
The primary purpose of the dose escalation part is to estimate the MTD and/or
to determine the recommended phase II dose (RP2D) of the orally administered
PI3K inhibitor BYL719 in combination with cetuximab. Once MTD/RP2D has been
determined, additional patients will be enrolled in Phase II to assess the
anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab
single-agent, and to further characterize the safety and tolerability of the
drug combination.
Study objective
Primary objective: Phase Ib: To estimate the MTD and/or RP2D of BYL719 in
combination with cetuximab. Phase II: To compare the efficacy of BYL719 plus
cetuximab in comparison with cetuximab monotherapy.
Secondary objective (major): safety and tolerability, PK.
PROTOCOL AMENDMENT 5 added primary objective for phase ib part
*Arm C: To compare the pharmacokinetics of the dispersible tablet formulation
of BYL719 in combination with cetuximab in patients with
RM HNSCC with Arm A
Study design
Open-label phase Ib dose escalation and randomized phase II study.
Approximately 111 patients (20 for phase Ib and 99 for phase II).
The aim of phase Ib (n~12) is to determine the MTD and/or RP2D of BYL719 in
combination with fixed-dose cetuximab. Cycles of 4 weeks. Cohorts of 3-6
patients. Bayesian logistic regression model.
ARM A: Patients with no swallowing dysfunction (BYL719 whole tablets +
cetuximab)
ARM B: Patients with swallowing dysfunction (crushed BYL719 tablets + cetuxmab)
PROTOCOL AMENDMENT 5:
added
ARM C: Patients with swallowing dysfunction with PEG-sonde or G-sonde (BYL719
dispers + cetuximab)
Phase II (n~99) will be performed with the highest well-tolerated dose of
BYL719 in combination with fixed dose (=SPC recommended dose).
ARM 1 and ARM 2: Randomization (2:1) to this combination or cetuximab in SPC
recommended dose as monotherapy. Cetuximab only as induction therapy allowed.
ARM1: Combination BYL719 + cetuximab (N=66)
ARM 2: Cetuximab monotherapy (N=33) -> cross-over to ARM 2B: Combination BYL719
+ cetuximab
ARM 3: prior cetuximab therapy in combination with platinum
ARM 3: Combinatie BYL719 + cetuximab (N=40)
Treatment until progression or unacceptable toxicity.
Follow-up for survival (phase II patients).
PROTOCO AMENDMENT 5
Added to PHASE IB part:
*Arm C: To compare the pharmacokinetics of the dispersible tablet formulation
of BYL719 in combination with cetuximab in patients with
RM HNSCC with Arm A
- Arm C will use a suspension administered via gastric feeding tube
(gastrostomy tube, G-tube), in patients with swallowing dysfunction
Intervention
Treatment with cetuximab in combination with BYL719 or cetuximab alone.
Phase Ib part: cetuximab (i.v. 400mg/m2 starting dose followed by weekly
250mg/m2) + BYL719 escalting dose (startdose = 300mg BYL719, oral daily
administration).
Phase II part: randomisation 2:1
Arm 1: ~66 patients BYL719 + cetuximab
Arm 2: ~33 patients cetuximab
Arm 3: ~40 patients BYL719 + cetuximab
PROTOCOL AMENDMENT 5
BYL719 is availableas film-coated tablets and dipsers (solutable in water)
Study burden and risks
Risk: Adverse events of study medication (BYL719 and cetuximab). The
combinations have not yet been tested in humans before.
Side effect seen in BYL719 sofar are hyperglycemia, nausea, fatigue, liver
enzyme abnormalities, vomiting, diarrhea, dyspepsia, erythema, flatulence,
hypertension, increased tendency to bruise, skin atrophy and hand-foot syndrome
The most important side effects of cetuximab (alone) are skin rash,
hypomagnesaemia, headache, diarrhea, infection, infusion reaction (an
allergy-like response, sometimes fatal), cardiopulmonary arrest and/or sudden
death, interstitial lung disease (scarring of the lung), kidney failure,
aseptic meningitis
Other risks caused by assessments during study: radiation due to scans and
X-rays, risks and inconvenience due to infusion of cetuximab and blooddraws as
local infections, pain and bleeding, risks and inconveniences due to
tumorbiopsies as bleeding and pain.
Burden:
Treatment cycles of 4 weeks with weekly cetuximab infusions.
6 visits during cycle 1 and 4 visits in the subsequent cycles. Visit duration
1-4 h. 2 visits (phase Ib, 9 samples of 2,5 ml each per occasion) en 1 visit
(phase II, 4 samples of 2,5 ml each) of 8-10 h (serial PK sampling) for BYL719
patients only.
Weekly blood sampling during cycle 1-2 and bi-weekly thereafter. 25-40 ml of
blood/cycle, except for cycle 1 (=50-110 ml).
ECGs: 4 during cycle 1, 2 during cycle 2, 1 per cycle thereafter.
Echocardiogram or MUGA-scan at screening and end of treatment.
Tumor evaluations at screening and every 6-8 weeks thereafter until disease
progression.
Tumor biopsy at screening and at disease progression.
Follow-up for survival (phase II patients only, phone call every 4 months).
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
- Age * 18 years
- Patients with histologically/cytologically-confirmed HNSCC
- Patients must be resistant to platinum-based chemotherapy, or be ineligible or intolerant to platinum-based therapy
- For Phase Ib only, at least 1 prior therapy for recurrent or metastatic disease
- For Phase II only, a maximum of 1 prior therapy for recurrent or metastatic disease
- Prior cetuximab or another 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
- Availability of tumor specimen (primary or metastatic, archival or fresh)
- At least one measurable or non-measurable lesion is required for patients enrolled in Phase Ib. Measurable disease is required for Phase II patients (as per RECIST 1.1 criteria)
- WHO Performance Status (PS) * 2.
- Adequate organ function and laboratory parameters
- Negative serum pregnancy test ;NEW
-For Arm 3, prior cetuximab incl. platinum as therapeutic setting and disease progression documented within 9 months of the last dose of cetuximab administered in that setting.
- Patients enrolled in Arm 3 must have amenable sites to biopsy;More detailed inclusion criteria see protocol section 5.2
Exclusion criteria
- Prior treatment with PI3K-inhibitors
- Patients with a prior serious infusion reaction to cetuximab
- Patients with primary central nervous system (CNS) tumor or CNS tumor involvement
- Clinically significant cardiac disease or impaired cardiac function
- Patients with diabetes mellitus
- Impaired GI function or GI disease that may signifincant alter the absorption of oral BYL719
- History of another malignancy within 2 years prior to starting study treatment ;More detailed exclusion criteria see protocol section 5.3
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-006017-34-NL |
| ClinicalTrials.gov | NCT01602315 |
| CCMO | NL42698.091.12 |