Clinical Trial EA3132

Chelsea Gehrig
DOS 741 Protocols & Studies in Radiation Oncology
EA3132

Phase II Randomized Trial of Radiotherapy With or Without Cisplatin for Surgically

Resected Squamous Cell Carcinoma of the Head and Neck with TP53 Sequencing

Eastern Cooperative Oncology Group (ECOG-ACRIN Cancer Research Group)

National Cancer Institute

ClinicalTrials.gov ID: NCT02734537

  Whether patients who are at risk of
recurrence and whose tumors have a
Purpose mutation in a gene p53 would also benefit
from chemoradiation after surgery vs. RT
alone
Why EA3132?

 Many Head and Neck

patients treated
 Challenging to plan
 Unique- are disruptive p53
mutations a high-risk factor
that would benefit from
chemoradiation?
 Mutated form of TP53 has
been implicated in more
than 50% of all cancers
What is p53?
 Protein encoded by the tumor suppressor gene TP53
 Prevents cells with damaged DNA from dividing
 Promotes cell death in damaged cells
 Mutated form of TP53 has been implicated in more than 50% of all cancers
Study Design

Phase II Interventional Randomized

Purpose: 189 March 29,

Treatment Participants 2016- present
Primary Objective

I. Evaluate the disease-free survival (DFS) of patients with stage III-IV

squamous cell carcinoma of the head and neck (SCCHN) and
disruptive p53 mutations after primary surgical resection followed by
post-operative radiation therapy (PORT) alone or PORT with
concurrent cisplatin.
 Ev aluate DFS of patients with
stage I II-IV SCCHN and non-
disruptiv e p53 mutations after
primary surgical resection
follow ed by PORT alone or PORT
w ith concurrent cisplatin
Ev aluate DFS of patients w ith Ev aluate toxicities of PORT
stage I II-IV SCCHN and p53 alone or PORT w ith concurrent
w ildtype after primary surgical cisplatin
resection followed by PORT
alone or PORT w ith concurrent
cisplatin

Secondary
objectives

Ev aluate p53 mutation as a I dentify potential genomic

predictive biomarker of survival alterations, in addition to TP53
benefit giv en post-operative mutations, that may be
concurrent radiation and dev eloped to a nov el
cisplatin treatment approach
  ≥ 18 years of age
 Pathologically proven diagnosis of squamous cell carcinoma
(including variants such as verrucous carcinoma, spindle cell
carcinoma, carcinoma not otherwise specified) of the head or
neck (oral cavity, oropharynx, hypopharynx, or larynx);
pathologic stage III or IVA (AJCC 8): T3–T4a, N0–3, M0 or T1–T2,
N1–3, M0

Patient  Total resection of the primary tumor with curative intent Note:
Patient is to be pre-registered to screening (step 0) and tissue
submitted to Foundation Medicine as soon as possible after
Inclusion surgery, to meet the 8-week deadline to register to step 1 after
surgery. Full assay minimum turnaround time is 17–24 days

Criteria  For oropharynx primary tumors, must have negative HPV status
of tumor based on p16 protein expression using
immunohistochemistry
 If history of curatively treated malignancy, disease-free for ≥ 2
years except for carcinoma in situ of cervix and/or non-
melanomatous skin cancer
  Per the operative report, gross total resection of the primary
tumor with curative intent completed within 8 weeks prior to
randomization
 Assessments completed ≤ 8 weeks prior to randomization:
examination by a head and neck surgeon, and chest x-ray (or
chest CT scan or CT/PET of chest or MRI) to rule out distant
metastatic disease

Patient  ECOG performance status 0–1 within 2 weeks prior to

randomization

Inclusion  Absolute neutrophil count >= 1,500/mm^3 (within 4 weeks prior

to randomization)

Criteria  Platelets >= 100,000/mm^3 (within 4 weeks prior to

randomization)
 Total bilirubin =< the upper limit of normal (ULN) (within 4 weeks
prior to randomization)
 Calculated creatinine clearance must be > 60 ml/min using the
Cockcroft-Gault formula (within 4 weeks prior to randomization)
  Positive margin(s) not superseded by additional
margin of tumor-negative tissue, nodal
extracapsular extension, and/or gross residual
disease after surgery
 Received chemotherapy or investigational therapy
within 2 years of surgical resection of the primary
tumor
Patient  Previous irradiation to head and neck that would
Exclusion result in overlap in radiation fields for current
disease
Criteria  Recurrent disease or multiple primaries
 Inter-current illness likely to interfere with protocol
therapy
 Pregnancy or breast-feeding
Head and neck cancer stages III-IVA
Stage III
The tumor fits one of the following
criteria:
❖ It is larger than 4 cm across, and
no cancer cells are present in
nearby structures, lymph nodes
or distant sites.
❖ It is any size but has not grown
into nearby structures or distant
sites. However, cancer cells are
present in one lymph node,
which is located on the same
side of the head or neck as the
primary tumor and is smaller
than 3 cm across.
Stage IVA
One of the following applies:
❖ The head and neck cancer tumor is any size and is
growing into nearby structures. Cancer cells may not
be present in the lymph nodes, or they may have
spread to one lymph node, which is located on the
same side of the head or neck as the primary tumor
and is smaller than 3 cm across. Cancer has not
spread to distant sites.
❖ The tumor is any size and may or may not have
invaded nearby structures. It has not spread to distant
sites, and one of the following is true:
 Cancer cells are present in one lymph node,
located on the same side of the head or neck as
the primary tumor and measuring 3-6 cm across.
 Cancer cells are present in one lymph node on
the opposite side of the head or neck and
measuring less than 6 cm across.
 Cancer cells are present in two or more lymph
nodes, all smaller than 6 cm across and located
on either side of the head or neck.
Study Arms
Arm A
 Patients undergo intensity-
modulated radiation therapy
(IMRT) once daily, 5 days per
week for 6 weeks in the absence
of disease progression or
unacceptable toxicity.
Arm B
 Patients undergo intensity-
modulated radiation therapy
once daily, 5 days per week and
receive cisplatin intravenously
over 1-2 hours weekly for 6 weeks
in the absence of disease
progression or unacceptable
toxicity.
Cisplatin

 Platinum-based compound
 Cytotoxic drug
 First synthesized in 1844
 Chemical structure
interpreted in 1893
 Scientific Investigation
began in the 1960’s
Radiation Treatment planning

 60 Gy total with 2 Gy fractions once-daily

 Treatment of PTV60 followed by 6 Gy boost is not permitted
 Begin Monday, Tuesday, or Wednesday
 IMRT technique using MV photons
 Calibration verified by IROC Houston (RPC)
 Immobilization device
 With or without contrast
 ≤ 3 mm slices
 IGRT recommended, weekly verification required
 Radiation Treatment planning

IMRT plan with 10 fields VMAT plan with two 360 arcs
Immobilization Devices
 Aquaplastic/thermosplastic mask
 Bite Block
 H&N mold/cusion
Benefits

 Adding chemotherapy could improve results with RT

 Kill tumors cells
 Stop division
 Prevent spread
 Doctors can see whether the p53 mutation may be a biomarker for better
results
Study Results

RECRUITMENT STATUS: ESTIMATED PRIMARY ESTIMATED STUDY

RECRUITING COMPLETION DATE: MAY COMPLETION DATE: MAY
1, 2022 1, 2027
References

1. Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of
the Head and Neck Who Have Undergone Surgery. ClinicalTrials.gov.
https://clinicaltrials.gov/ct2/show/NCT02734537. Accessed June 29th, 2021.
2. Radiation Therapy with or without Cisplatin in Treating Patients with Stage III-IVA Squamous Cell Carcinoma of
the Head and Neck Who Have Undergone Surgery. National Cancer Institute. https://www.cancer.gov/about-
cancer/treatment/clinical-trials/search/v?id=NCI-2015-01911&loc=0&q=ea3132&rl=. Accessed June 29th, 2021.
3. EA3132 Educational Material. ECOG-ACRIN cancer research group. https://ecog-acrin.org/clinical-
trials/ea3132-educational-materials. Accessed June 29th, 2021.
4. Dasari S., Tchounwou P.B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol.
2014;740:364-378. doi:10.1016/j.ejphar.2014.07.025
5. TP53 gene. Britannica. https://www.britannica.com/science/TP53. Accessed June 30th, 2021.
6. Tumor Suppressor gene. Britannica. https://www.britannica.com/science/tumor-suppressor-gene#ref1078159.
Accessed June 30th, 2021.
7. Head and neck cancer stages. Cancer Treat ment Centers of America.
https://www.cancercenter.com/cancer-types/head-and-neck-cancer/stages. Updat ed June 29th, 2021.
Accessed June 30th, 2021.