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