Clinical trial NCT02051751: A Study to Evaluate the Potential Benefit of the Addition of BYL719 to Paclitaxel in the Treatment of Breast Cancer and Head-and-neck Cancer
Official title: A Phase Ib Open Label Dose Finding Study of BYL719 in Combination With Paclitaxel in Advanced Solid Tumors Followed by Two Expansion Phases in Locally Advanced/Metastatic Chemotherapy Naive HER2 Negative Breast Cancer Patients (HER2- mBC) and in Recurrent and Metastatic Head-and-neck Squamous Cell Carcinoma Patients (HNSCC) Pre-treated With Platinum Based Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms, Breast Neoplasms, Head and Neck Neoplasms
Keywords: Solid tumors, Head and neck non squamous cell carcinoma, breast cancer, PI3K inhibitor, BYL719, paclitaxel
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-01-31
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Dose escalation part:to determine the highest dose of BYL719 administered on a daily basis when given in combination with weekly paclitaxel Dose escalation part: to confirm the safety and tolerability of the BYL719 and paclitaxel combination


Eligibility criteria: Inclusion criteria For entire trial:

1. - Adult \> or = 18 years old
2. - has signed the Informed Consent Form (ICF)
3. - has at least one measurable or non-measurable disease as per RECIST 1.1
4. - has tumor tissue available for the analysis as described in the protocol
5. - has adequate bone marrow and organ function as defined in the protocol
6. - is able to swallow and retain oral medication for the dose escalation part, ALL above PLUS
7. - has a histologically-confirmed, advanced unresectable solid tumors who have progressed on standard therapy (or not been able to tolerate) within three months before screening/baseline visit or for whom no standard anticancer therapy exists.
8. - has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 For dose expansion part, patient has ALL of above first six criteria PLUS either: 9- has a histologically/cytologically-confirmed HNSCC as detailed in the protocol and an ECOG performance status ≤ 1 or:

   * Patient is a Female with a histologically and/or cytologically confirmed diagnosis of breast cancer as detailed in the protocol and an ECOG performance status ≤ 1

Common exclusion criteria to Dose escalation and Dose expansion parts:

1. - has received previous treatment with a PI3K or AKT inhibitor as described in the protocol
2. - has a known hypersensitivity to paclitaxel or other products containing Cremophor
3. - has a contraindication to use the standard pre-treatment for paclitaxel
4. - has a primary central nervous system (CNS) tumor or CNS tumor involvement as detailed in the protocol
5. - has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
6. - has received radiotherapy \> or = 4 weeks prior to starting study drugs, with exception of palliative radiotherapy, who has not recovered from side effects of such therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was irradiated
7. - has peripheral sensory neuropathy with functional impairment (CTC grade 2 neuropathy or higher)
8. - has undergone major surgery ≤ 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure
9. - has a clinically significant cardiac disease or impaired cardiac function as detailed in the protocol
10. - is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
11. - has diabetes mellitus requiring insulin treatment and/or with clinical signs
12. - has impaired gastrointestinal (GI) function or GI disease as described in the protocol
13. - has a known positive serology for human immunodeficiency virus (HIV), active Hepatitis B, and/or active Hepatitis C infection
14. - has any other condition that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures
15. - is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzymes CYP3A or CYP2C8 as detailed in the protocol
16. - is currently receiving treatment with agents that are metabolized solely by CYP3A and/or have a narrow therapeutic window
17. - has a history of another malignancy within 2 years prior to starting study treatment, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix
18. - Patient has a history of non-compliance to medical regimen or inability to grant consent
19. - Pregnant or nursing (lactating) women
20. - does not apply highly effective contraception during the study and through the duration as defined in the protocol

For the HNSCC patient's cohort additional exclusion criteria are:

21- Treatment with more than one prior chemotherapy for recurrent/metastatic disease as detailed in the protocol 22- Prior taxane treatment for metastatic disease additional exclusion criteria for breast cancer patients' cohort:

- has received any prior cytotoxic therapy for the inoperable locally advanced (recurrent or progressive) or metastatic disease, or who had a progression/recurrent disease within 6 months after completion of an adjuvant/neoadjuvant therapy as described in the protocol

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Dose escalation : Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1 (28 days)
measure: Dose expansion : Number of patients with adverse events as a measure of safety and tolerability
timeFrame: Screening, every 28 days until 30 days after last dose
Secondary outcomes:
measure: Dose escalation:Number of patients with adverse events as a measure of safety and tolerability
timeFrame: Screening, every 28 days until 30 days after last dose
measure: Dose escalation : BYL719 and Paclitaxel Plasma concentrations
timeFrame: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9
measure: Dose expansion: Clinical benefit Rate in the breast cancer cohort
timeFrame: Baseline, every 8 weeks (Breast cancer patients) from start of treatment until first documented disease progression up to 2 years
measure: Dose expansion: Progression free survival
timeFrame: Baseline, every 6 weeks (head-and-neck squamous cell carcinoma (HNSCC) patients) or every 8 weeks (Breast cancer patients) from start of treatment until first documented disease progression up to 2 years
measure: Dose expansion: Overall response rate
timeFrame: Baseline, every 6 weeks (HNSCC patients) or every 8 weeks (Breast cancer patients) from start of treatment until first documented disease progression up to 2 years
measure: Dose expansion : Duration of Response
timeFrame: Baseline, every 6 weeks (HNSCC patients) or every 8 weeks (breast cancer patients) from start of treatment until first documented disease progression up to 2 years
measure: Dose expansion: Plasma pharmacokinetics of BYL719 given in combination with paclitaxel in breast cancer and HNSCC patients
timeFrame: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 15, and Day 1 of each subsequent Cycle
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Lafayette
country: United States
facility: Horizon Oncology Center BioAdvance
state: Indiana
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Rodon J, Curigliano G, Delord JP, Harb W, Azaro A, Han Y, Wilke C, Donnet V, Sellami D, Beck T. A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget. 2018 Aug 3;9(60):31709-31718. doi: 10.18632/oncotarget.25854. eCollection 2018 Aug 3.