Clinical Trials /

Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck (TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)]

NCT03292250

Description:

Open, multicenter, single arm, phase II, biomarker driven umbrella trial for head and neck squamous cell carcinoma

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck (TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)]
  • Official Title: Public-interest Multicenter Umbrella Trial Based on Genetic Analysis in Korean Head and Neck Cancer and Esophageal Cancer Patient - Part 1 (HNSCC)]

Clinical Trial IDs

  • ORG STUDY ID: KCSG-TRIUMPH
  • NCT ID: NCT03292250

Conditions

  • HNSCC
  • Head and Neck Neoplasms

Interventions

DrugSynonymsArms
BYL719Arm1: BYL719
PoziotinibArm2: Poziotinib
NintedanibArm3: Nintedanib
AbemaciclibArm4: Abemaciclib
Durvalumab,TremelimumabArm5: Durvalumab,Tremelimumab

Purpose

Open, multicenter, single arm, phase II, biomarker driven umbrella trial for head and neck squamous cell carcinoma

Detailed Description

      This study will be conducted as a part of umbrella trial by Korean Cancer Study Group. The
      brief scheme of this umbrella trial is as follows:

      R/M HNSCC 2nd line

        1. PI3K inhibitor - BYL719 (from Norvatis)

        2. EGFR/HER2 inhibitor - poziotinib (from Hanmi pharmaceutical)

        3. FGFR inhibitor - nintedanib (from Boehringer ingelheim)

        4. Cell cycle (CDK4/6) inhibitor - abemaciclib (from Lily)

        5. Others- anti PD1/PD-L1 - durvalumab+/-tremelimumab (from AZ)

      During or after palliative 1st line platinum based chemotherapy, we will perform prescreening
      NGS based molecular characterization. The molecular characterization will be done by
      following three methods.

        -  NGS : Agilent SureSelect Target Enrichment (245 genes)

        -  Nanostring nCounter including immune signature

        -  IHC : PD-L1, CD8 TIL, p16

      Mutation will be analyzed by NGS, fusion and amplification will be determined by Nanostring
      methods, and PD-L1/p16 status will be determined by immunohistopathology. Molecular tumor
      board to determine characterization will be held for every patients. Once each patients have
      relevant genetic pathway, the patients will be allocated each treatment arm (see below
      figure). If the patients have no relevant genetic alteration, such a patients will allocated
      to durvalumab+/- tremelimumab arm regardeless of PD-L1 positivity. If the patients who
      allocated to poziotinib, BYL719, nintedanib, and abemaciclib experience disease progression
      but still meet the inclusion/ exclusion criteria for durvalumab+/- tremelimumab arm, the
      cross over to durvalumab+/- tremelimumab arm will be permitted. Vice versa (cross over from
      durvalumab+/- tremelimumab arm to another arms) is not permitted.
    

Trial Arms

NameTypeDescriptionInterventions
Arm1: BYL719ExperimentalExperimental: BYL719 BYL719 is an oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of compounds.
  • BYL719
Arm2: PoziotinibExperimentalExperimental:Poziotinib Poziotinib is a pan-HER tyrosine kinase inhibitor.(oral class)
  • Poziotinib
Arm3: NintedanibExperimentalNintedanib is a potent small molecule triple receptor tyrosine kinase inhibitor (PDGFR, FGFR 1-3,VEGFR 1-3 ,VEGFR- 2) is considered to be the crucial receptor involved in initiation of the formation as well as the maintenance of tumour vasculature.(oral class)
  • Nintedanib
Arm4: AbemaciclibExperimentalAbemaciclib represents a selective and potent small molecule CDK4 and CDK6 dual inhibitor with broad antitumor activity in preclinical pharmacology models.(oral class)
  • Abemaciclib
Arm5: Durvalumab,TremelimumabExperimentalDurvalumab is a human immunoglobulin (Ig) G1 kappa (IgG1κ) monoclonal antibody (mAb) that blocks the interaction of PD-L1 with PD-1 on T-cells and CD80 on immune cells and is engineered to reduce antibody-dependent cell-mediated cytotoxicity.(IV class) Tremelimumab is specific for human CTLA-4; cluster of differentiation a cell surface receptor that is expressed primarily on activated T cells and acts to inhibit their activation.(IV class)
  • Durvalumab,Tremelimumab

Eligibility Criteria

        Common Inclusion Criteria: The following criteria must all be met.

          -  Histologically or cytologically confirmed recurrent or metastatic SCCHN

          -  Ineligibility for local therapy (surgery or radiation for curative intent)

          -  Prior palliative chemotherapy including platinum-based chemotherapy. When recurred
             within 6 months of definitive/neoadjuvant/adjuvant chemo- or chemoradiation, the
             chemotherapy is considered a line of palliative chemotherapyAt least one measurable
             lesion by RECIST ver 1.1

          -  Age ≥20

          -  ECOG performance status of 0-1

          -  Adequate organ function for treatment

               -  Absolute neutrophil count (ANC) ≥1500 cells/mm3

               -  Platelets ≥100,000 cells/mm3

               -  Hemoglobin ≥ 9 g/dL.

               -  Serum creatinine <1.5 x institution upper limit of normal

               -  Bilirubin ≤1.5 x upper limit of normal (ULN)

               -  AST (SGOT) ≤3.0 x ULN

               -  ALT (SGPT) ≤3.0 x ULN

          -  At least one lesion that is measurable according to the RECIST 1.1 criteria by CT or
             MRI

          -  The patient has provided signed informed consent and has a compliance to follow the
             study protocol.

        Common Inclusion Criteria: Patients eligible for this study should not meet any of the
        following criteria:

          -  Nasopharyngeal carcinoma

          -  Major surgery within 4 weeks prior to initiating study treatment

          -  Patients who have received prior systemic chemotherapy, immunotherapy or study drug
             within 4 weeks (Exclusion of conventional radiotherapy for non-target lesions within 2
             weeks prior to enrollment)

          -  Pregnant woman, Breast-feeding woman

          -  Females who were not screened for pregnancy or had positive results. (Women are
             considered post-menopausal and not of child bearing potential if they have had 12
             months of amenorrhea or have had surgical bilateral oophorectomy or Age ≥60

          -  Previous or concomitant malignant disease, except adequately treated basal cell cancer
             of the skin or cervical cancer in situ, superficial bladder tumors (Ta, Tis & T1) or
             any cancer curatively treated > 3 years prior study entry

          -  Other severe acute or chronic medical condition or laboratory abnormality that may
             increase the risk associated with trial participation or investigational product
             administration or may interfere with the interpretation of trial results and, in the
             judgment of the investigator, would make the patient inappropriate for entry into this
             trial (infection/inflammation, intestinal obstruction, social/psychological
             complications)

          -  Patients with significant cardiovascular disease or within AMI 12 months, (Congestive
             heart failure or Any significant ventricular arrhythmia)

          -  Patients who received organ transplants requiring immunosuppressive therapy

          -  Patients with HBsAg, anti-HCV, HIV-positive patients or other uncontrolled infectious
             diseases

               -  However, Arm1-Arm3 Inactivated hepatitis B carriers using appropriate
                  prophylactic antiviral agents can be listed at the discretion of the investigator

               -  Arm5: An active HBV carrier who has received HBV DNA <100 IU / mL at the time of
                  screening, has received appropriate prophylactic antiviral treatment and
                  continues to receive treatment with an antiviral agent during the trial can be
                  registered.

        Specific Inclusion Exclusion Criteria: In addition to the common Inclusion / exclusion
        criteria, the specific drug Inclusion / exclusion criteria for the drug study should be
        met.

        Arm 1: BYL719

        BYL719 Specific Inclusion Criteria

          -  Patients with relevant genetic alterations including PI3K pathway alteration or those
             by physician's discretion based on next generation sequencing (NGS).

          -  Uncontrolled, untreated brain metastasis. Patients with treated/controlled and
             asymptomatic CNS metastases may participate in this trial. The patient must have
             completed any prior treatment for CNS metastases ≥ 28 days (must include radiotherapy
             and/or surgery) and, if on corticosteroid therapy, should be receiving a stable low
             dose (e.g. dexamethasone 4 mg or equivalent dose of another corticosteroid for at
             least 14 days before start of study treatment).

          -  Life expectancy of at least 12 weeks

        BYL719 Specific Exclusion Criteria

          -  Prior treatment with AKT. mTOR PI3K pathway inhibitors

          -  Patient who cannot take the oral drug

          -  Impaired GI function or GI disease that may significantly alter the absorption of oral
             BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea,
             malabsorption syndrome, or small bowel resection)

          -  Other severe acute or chronic medical condition or laboratory abnormality that may
             increase the risk associated with trial participation or investigational product
             administration

          -  Clinically significant cardiac disease or impaired cardiac function, such as:

               -  Congestive heart failure (CHF) requiring treatment (New Yort Heart Association
                  (NYHA) Grade ≥ 2)

               -  left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated
                  acquisition (MUGA) scan or echocardiogram

               -  uncontrolled arterial hypertension defined by blood pressure > 140/100 mmHg at
                  rest (average of 3 consecutive readings)

               -  History or current evidence of clinically significant cardiac arrhythmias,
                  arterial fibrillation and/or conduction abnormality, e.g. congenical long QT
                  syndrome, high grade/complete AV-blockage

               -  Acute coronary syndromes (including myocardial infarction, unstable angina,
                  coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3
                  months prior to screening, QTcF> 480 msec on screening ECG

          -  Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs
             or with FPG ≥ 140 mg/dL/7.8mmol/L, or history of documented steroid-induced diabetes
             mellitus.

        Arm 2: poziotinib

        poziotinib Specific Inclusion Criteria

          -  Patients with relevant genetic alterations including EGFR/HER2 pathway alteration or
             those by physician's discretion based on next generation sequencing (NGS).

        poziotinib Specific Exclusion Criteria

          -  Previous treatment with small molecule EGFR tyrosine kinase inhibitors (Cetuximab is
             permitted)

          -  Patients with uncontrolled CNS metastatic involvement. However, corticosteroids should
             be discontinued at least 2 weeks before clinical trials, except for radiologic and
             neurologically stable cases for more than 4 weeks.

          -  Patients with known interstitial lung disease

          -  Patients with uncontrolled or significant cardiovascular disease (AMI ,Unstable angina
             within 6 months, NYHA Class III, IV Congestive heart failure or left ventricular
             ejection fraction below local institutional lower limit of normal or below 50%,
             Congenital long QT syndrome, Any significant ventricular arrhythmia, Any uncontrolled
             second or third degree heart block, Uncontrolled hypertension)

          -  Any clinically significant gastrointestinal abnormalities which may impair intake or
             absorption of the study drug

        Arm 3: nintedanib

        nintedanib Specific Inclusion Criteria

          -  Patients with relevant genetic alterations including FGFR athway alteration or those
             by physician's discretion based on next generation sequencing (NGS).

          -  Life expectancy of at least 12 weeks

        nintedanib Specific Exclusion Criteria

          -  Prior treatment with FGFR pathway inhibitors

          -  Recent bleeding history, major vessel invasion of tumour

          -  Patient who cannot take the oral drug

          -  Patients with active brain metastases (defined as stable for <4 weeks, no adequate
             previous treatment with radiotherapy, symptomatic, or requiring treatment with
             anticonvulsants). Patients with treated/controlled and asymptomatic CNS metastases may
             participate in this trial.

          -  Clinically significant cardiac disease or impaired cardiac function, such as:

               -  Congestive heart failure (CHF) requiring treatment (New Yort Heart Association
                  (NYHA) Grade ≥ 2)

               -  left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated
                  acquisition (MUGA) scan or echocardiogram

               -  uncontrolled arterial hypertension defined by blood pressure > 140/100 mmHg at
                  rest (average of 3 consecutive readings)

               -  History or current evidence of clinically significant cardiac arrhythmias,
                  arterial fibrillation and/or conduction abnormality, e.g. congenical long QT
                  syndrome, high grade/complete AV-blockage

               -  Acute coronary syndromes (including myocardial infarction, unstable angina,
                  coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3
                  months prior to screening, QTcF> 480 msec on screening ECG

          -  Patients who are 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

          -  Therapeutic anticoagulation (except low-dose heparin or heparin flush in the catheter)
             or antiplatelet therapy (except for acetylsalicylic acid <325 mg / day)

        Arm 4: abemaciclib

        abemaciclib Specific Inclusion Criteria

          -  p16 negative and genetic alterations in CDK4/6 pathway

          -  Patients who received chemotherapy must have recovered (Common Terminology Criteria
             for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
             residual alopecia or Grade 2 peripheral neuropathy prior to screening. A washout
             period of at least 21 days is required between last chemotherapy dose and screening
             (provided the patient did not receive radiotherapy).

          -  Patients who received adjuvant radiotherapy must have completed and fully recovered
             from the acute effects of radiotherapy. A washout period of at least 14 days is
             required between end of radiotherapy and randomization

        abemaciclib Specific Exclusion Criteria

          -  Prior treatment with CDK4/6 pathway inhibitors

          -  Recent significant bleeding history and major vessel invasion of tumor

          -  Pregnant woman, Breast-feeding woman

               -  If a female of childbearing potential, must have a negative serum pregnancy test
                  within 7 days of the first dose of abemaciclib and agree to use a medically
                  approved contraceptive method during the treatment period and for 3 months
                  following the last dose of abemaciclib.

          -  If a male, must agree to use a reliable method of birth control and to not donate
             sperm during the study and for at least 3 months following the last dose of
             abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier
             method. If condoms are used as a barrier method, a spermicidal agent should be added
             as a double barrier protection.

          -  The patient has serious preexisting medical condition(s) that would preclude
             participation in this study (for example, interstitial lung disease, severe dyspnea at
             rest or requiring oxygen therapy, history of major surgical resection involving the
             stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a
             preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).

          -  Patient who cannot take the oral drug

          -  Patient who have an active systemic fungal and/or known viral infection (for example,
             human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C
             antibodies)

        Arm 5: durvalumab +/- tremelimumab

        durvalumab +/- tremelimumab Specific Inclusion Criteria

          -  NGS analysis on the molecular tumor board showed that there was no mutation
             corresponding to Arm 1 ~ 4 or Patients who were treated with Arm 1 ~ 4 and progressed
             to disease and who satisfied Arm5 criteria (Arm 1 ~ 4 allow cross over to Arm 5, but
             not the reverse.)

        durvalumab +/- tremelimumab Specific Exclusion Criteria

          -  Previous treatment with CTLA-4 , PD-1 or PDL-1 inhibitors

          -  Symptomatic brain metastasis

          -  Patients with known interstitial lung disease

          -  Systemic immunosuppressive therapy

          -  Active autoimmune disease 7 - Body weight <30kg

          -  Other severe acute or chronic medical condition or laboratory abnormality that may
             increase the risk associated with trial participation

          -  12-Lead electrocardiogram (ECG) with abnormal tracing or clinically significant
             changes that require medical intervention

          -  History of treatment with live vaccine within 30 days of drug administration for
             clinical trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate (DCR)
Time Frame:24 months
Safety Issue:
Description:Arm 1: RECIST version 1.1

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:24 months
Safety Issue:
Description:RECIST version 1.1
Measure:Progression-free survival (PFS)
Time Frame:24 months
Safety Issue:
Description:RECIST version 1.1
Measure:Overall survival (OS)
Time Frame:24 months
Safety Issue:
Description:Overall Survival is defined as the time from first dose to death due to any cause. Through the follow-up within 30 days after study completion or termination of the last subject, death and date of death will be checked for subject alive during treatment period
Measure:Time to progression (TTP)
Time Frame:24 months
Safety Issue:
Description:RECIST version 1.1
Measure:Quality of life assessment
Time Frame:24 months
Safety Issue:
Description:FACT-H&N (Version 4.0)
Measure:Duration of response
Time Frame:24 months
Safety Issue:
Description:RECIST version 1.1
Measure:Toxicity: Number of patients with treatment-related AE as assessed by NCI CTCAE version 4.03
Time Frame:24 months
Safety Issue:
Description:number of patients with treatment-related AE as assessed by NCI CTCAE version 4.03
Measure:biomarker
Time Frame:24 months
Safety Issue:
Description:NGS, nanostring

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seoul National University Hospital

Trial Keywords

  • NGS
  • Nanostring
  • Biomarker Driven Umbrella Trial
  • BYL719,poziotinib, abemaciclib, nintedanib
  • Durvalumab + Tremelimumab Combination Treatment

Last Updated