Title
Randomized Phase II/III Trial of Radiation with Cisplatin at 100 mg/m2 Every Three Weeks versus Radiation with Weekly Cisplatin at 40 mg/m2 for Patients with Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck

Description
This phase II/III trial compares the effect of the combination of high-dose cisplatin every three weeks and radiation therapy versus low-dose cisplatin weekly and radiation therapy for the treatment of patients with locoregionally advanced head and neck cancer. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out if low-dose cisplatin given weekly together with radiation therapy is the same or better than high-dose cisplatin given every 3 weeks together with radiation therapy in treating patients with head and neck cancer.

Objective
PRIMARY OBJECTIVES:
I. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with low-dose cisplatin weekly is non-inferior to radiation with high-dose cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III)

SECONDARY OBJECTIVES:
I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms .
III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (primary PRO), between arms.
V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms.
VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective).
VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms.

EXPLORATORY OBJECTIVE:
I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival.
OUTLINE: Patients are assigned to 1 of 2 groups.
GROUP I (NON-OROPHARYNGEAL CANCER [OPC]/p16-NEGATIVE OPC): Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV once a week (QW) during radiation therapy in the absence of disease progression or unacceptable toxicity.
GROUP II (p16-POSITIVE OPC/CANCER OF UNKNOWN PRIMARY [CUP]): Patients are randomized to 1 of 2 arms.
ARM III: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin IV Q3W (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.
ARM IV: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV QW during radiation therapy in the absence of disease progression or unacceptable toxicity.

Treatment Experimental: ARM I (high-dose cisplatin, radiation therapy)
Experimental: Arm II (low-dose cisplatin, radiation therapy)
Experimental: Arm III (high-dose cisplatin, radiation therapy)
Experimental: Arm IV (low-dose cisplatin, radiation therapy)

Key Eligibility For full study eligibility, see this study's ClinicalTrials.gov record.

Applicable Disease Sites
Head and Neck; Unknown Sites

Participating Institutions
Johnson Creek, UW Cancer Center; UW Cancer Center at ProHealth; UW Health Carbone Cancer Center Rockford; UW Health Eastpark Medical Center; UW Health University Hospital; Wm. S. Middleton Memorial VA Hospital