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Study of Safety & Efficacy of the Combination of LJM716 & BYL719 in Patients With Previously Treated Esophageal Squamous Cell Carcinoma (ESCC)

Phase 1
Completed
Conditions
Esophageal Squamous Cell Carcinoma
Interventions
Registration Number
NCT01822613
Lead Sponsor
Novartis Pharmaceuticals
Brief Summary

To study the safety and efficacy of the combination of LJM716 and BYL719 against currently available treatments of physician's choice in previously treated esophageal squamous cell carcinoma patients.

Detailed Description

The study design included a Phase 1b dose escalation portion to define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the combination of LJM716 and alpelisib, followed by an open-label, randomized Phase 2 part to compare anti-tumor activity of LJM716-alpelisib combination versus physician's choice of second-line therapy (paclitaxel, docetaxel, irinotecan). However, the phase 2 part was not conducted as the study was terminated early due to limited anti-tumor activity with LJM716-alpelisib combination observed in phase 1b.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
48
Inclusion Criteria
  • Histologically confirmed esophageal squamous cell carcinoma (ESCC)
  • No more than one prior chemotherapy regimen for recurrent or metastatic ESCC (for Phase II only).
  • Progression during or after platinum-based therapy for recurrent or metastatic ESCC, or recurrence within 6 months of platinum-based chemotherapy or chemoradiotherapy for localized disease.
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Exclusion Criteria
  • Patients who received prior phosphoinositide-3-kinase (PI3K) inhibitor or anti-receptor tyrosine-protein kinase erbB-3 (ERBB3 or HER3) antibody treatment, including bi-specific antibodies with HER3 as one of the targets (patients with prior exposure to pertuzumab or epidermal growth factor receptor (EGFR)-targeted agents are eligible)
  • Patients who do not have an archival or fresh tumor sample (or sections of it) available or readily obtainable.
  • Patients with central nervous system (CNS) metastatic involvement.
  • Patients who have received prior systemic anti-cancer treatment, such as cyclical chemotherapy or biological therapy within a period of time that is shorter than the cycle length used for that treatment (e.g. 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment.
  • Patients who have received definitive radiotherapy ≤ 4 weeks prior to starting study drug, who have not recovered from side effects of such therapy and/or from whom ≥ 30% of the bone marrow was irradiated.
  • Other protocol-defined inclusion/exclusion criteria may apply.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
LJM716-BYL719 armLJM716approximately 42 previously treated esophageal squamous cell carcinoma (ESCC) patients will be enrolled to the LJM716-BYL719 combination arm to evaluate the anti-tumor activity and further assess the safety, tolerability and anti-tumor activity of the combination versus current therapies (physician's choice of paclitaxel, docetaxel or irinotecan).
LJM716-BYL719 armBYL719approximately 42 previously treated esophageal squamous cell carcinoma (ESCC) patients will be enrolled to the LJM716-BYL719 combination arm to evaluate the anti-tumor activity and further assess the safety, tolerability and anti-tumor activity of the combination versus current therapies (physician's choice of paclitaxel, docetaxel or irinotecan).
Paclitaxel, Docetaxel or Irinotecan armDocetaxelapproximately 42 previously treated esophageal squamous cell carcinoma (ESCC) patients will be enrolled to the Paclitaxel, Docetaxel or Irinotecan arm (physician's choice arm) to evaluate the anti-tumor activity and further assess the safety, tolerability and anti-tumor activity of the LJM716-BYL719 combination versus current therapies (physician's choice of paclitaxel, docetaxel or irinotecan).
Paclitaxel, Docetaxel or Irinotecan armPaclitaxelapproximately 42 previously treated esophageal squamous cell carcinoma (ESCC) patients will be enrolled to the Paclitaxel, Docetaxel or Irinotecan arm (physician's choice arm) to evaluate the anti-tumor activity and further assess the safety, tolerability and anti-tumor activity of the LJM716-BYL719 combination versus current therapies (physician's choice of paclitaxel, docetaxel or irinotecan).
Paclitaxel, Docetaxel or Irinotecan armIrinotecanapproximately 42 previously treated esophageal squamous cell carcinoma (ESCC) patients will be enrolled to the Paclitaxel, Docetaxel or Irinotecan arm (physician's choice arm) to evaluate the anti-tumor activity and further assess the safety, tolerability and anti-tumor activity of the LJM716-BYL719 combination versus current therapies (physician's choice of paclitaxel, docetaxel or irinotecan).
Primary Outcome Measures
NameTimeMethod
Phase Ib primary outcome measure: Incidence rate of dose limiting toxicities (DLTs).approximately 8 months

The open-label dose escalation part of the study will be guided by a well-established statistical method/model to estimate the maximum tolerated dose(s) and/or Recommended Phase II Dose (s) guided by the safety (incidence of dose limiting toxicities), efficacy, pharmacokinetics and pharmacodynamics data.

Phase II primary outcome measure: Progression free survival (PFS)Every 6 weeks from the date of the baseline computed-tomography (CT) scan until the date of first documented evidence of disease progression or date of death, whichever comes first, assessed up to 24 months.

Progression-free survival is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate assessment.

Secondary Outcome Measures
NameTimeMethod
Safety and tolerability of the LJM716-BYL719Every 21 days from the date of the baseline visit until the end of study visit (about 5 months)

This will be assessed by looking at the number of Adverse Events (AEs), serious AEs (SAEs) changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.

Overall survival (OS) per RECIST 1.1 (for Ph 1b )Every 21 days from the date of the baseline computed tomography (CT) scan until the end of treatment visit (about 4 months)

Overall survival will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Progression free survival (PFS) per RECIST 1.1 (Ph 1b )Every 21 days from the date of the baseline computed tomography (CT) scan until the end of study visit (about 5 months)

Progression free survival will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Best overall response (BOR), per RECIST 1.1 (Ph 1b )Every 21 days from the date of baseline computed tomography (CT) scan until end of treatment visit (about 4 months)

BOR will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Overall response rate (ORR) per RECIST 1.1 (Ph 1b )Every 21 days from the date of the baseline computed tomography (CT) scan until the end of treatment visit (about 4 months)

Overall response rate will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Duration of response (DOR) per RECIST 1.1 (Ph 1b )Every 21 days from the date of the baseline computed tomography (CT) scan until the end of treatment visit (about 4 months)

Duration of response will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Disease control rate (DCR) per RECIST 1.1 (Ph 1b )Every 21 days from the date of the baseline computed tomography (CT) scan until the end of treatment visit (about 4 months)

Disease control rate will be used to further assess the anti-tumor activity of LJM716-BYL719 combination versus Paclitaxel, Docetaxel or Irinotecan.

Plasma concentration versus time profiles Plasma PK parameters of LJM716, BYL719Baseline, 2hr,4hr,8hr,24hr,48hr,96hr, 168 hr, every 21 days for 10 cycles (21 days each) and at end of treatment (about 4 months)

Plasma concentration versus time profiles Plasma PK parameters will be used to characterize the PK profiles of LJM716 and BYL719 when used in combination

Trial Locations

Locations (4)

Novartis Investigative Site

🇬🇧

Manchester, United Kingdom

University of Chicago Medical Center Dept of Onc

🇺🇸

Chicago, Illinois, United States

Karmanos Cancer Institute Dept of Onc

🇺🇸

Detroit, Michigan, United States

University of Texas/MD Anderson Cancer Center Gastrointestinal Med. Oncology

🇺🇸

Houston, Texas, United States

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