Onalespib in Treating Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck Receiving Radiation Therapy and Cisplatin

PRIMARY OBJECTIVES:

I. To determine the safety and recommended phase II dose (RP2D) of onalespib (AT13387) in
combination with concurrent cisplatin and radiotherapy in patients with locoregionally
advanced squamous cell carcinoma of the head and neck (LA-SCCHN). (Dose Escalation Phase) II.
To preliminarily evaluate the safety and preliminary efficacy of AT13387 in combination with
concurrent cisplatin and radiotherapy in patients with LA-SCCHN. (Dose Expansion Phase)

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of AT13387 in combination with cisplatin and
radiotherapy.

II. To evaluate the pharmacokinetics of cisplatin in combination with AT13387 and
radiotherapy.

III. To assess for pharmacodynamics biomarkers for proof-of-mechanism. IIV. To assess for
potential predictive biomarkers of efficacy. V. To document the toxicities associated with
the administration of AT13387 in combination with cisplatin and radiotherapy in patients with
LA-SCCHN.

VI. To explore and characterize predictive biomarkers for individual cancer patients
utilizing genomic sequencing technologies.

VII. To provide preliminary disease-free survival, locoregional control, distant
metastases-free survival, and overall survival.

OUTLINE: This is a dose-escalation study of onalespib.

Patients receive onalespib intravenously (IV) over 1 hour on days -7, 3, 10, 24, 31, and 38
and cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, 36, and 43. Patients also undergo IMRT
once daily (QD), 5 days a week over 7 weeks for a total of 35 fractions. Treatment continues
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 8 weeks, every 3 months for
1 year, and then every 6 months for 1 year. Beyond the first 2 years, patients may be
followed up every 6 months for up to 3 years per institutional standards.

Inclusion Criteria:

- Patients must have a histologically or cytologically confirmed, previously untreated
squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx

- Tumors must be staged T1-4, N2b-3, M0 (human papillomavirus positive [HPV]+ or HPV
negative [-]); patients with HPV+ tumors should have at least one high risk feature
such as T4, N3, or smoking history of > 10 pack years

- The disease must be considered to be potentially curable by combined radiotherapy and
cisplatin based chemotherapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Life expectancy of greater than 6 months

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin >= 9 g/dL

- Platelets >= 100 x 10^9/L

- Serum creatinine =< 1.5 mg/dL (=< 120 umol/L) OR calculated creatinine clearance
(Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50
mL/min

- Bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) =< 2.5 x ULN

- Alanine aminotransferase (ALT) =< 2.5 x ULN

- Proteinuria =< +1 on dipstick or =< 1 gram/24 hours

- Corrected QT using the Fridericia formula (QTcF) < 470 msec

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, during
the study participation, and for three months after the last dose of the drug; women
of child-bearing potential must have a negative serum pregnancy test within 14 days
prior to registration and agree to use effective contraception throughout the
treatment period and for 3 months after the last dose of study treatment; should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately; men
with a female partner of childbearing potential must have either had a prior vasectomy
or agree to use effective contraception; males should avoid fathering children during
and for at least three months after therapy is completed

- Ability to understand and the willingness to sign a written informed consent document

- Available for long-term follow-up of their disease after treatment

Exclusion Criteria:

- Patients with nasopharyngeal, paranasal sinus, skin, or unknown primary site disease

- Presence of distance metastases (M1)

- History of another malignancy; exception: patients who have been disease-free for > 3
years, or patients with a history of completely resected non-melanoma skin cancer
and/or patients with indolent secondary malignancies, are eligible; consult the Cancer
Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second
malignancies meet the requirements specified above

- Previous head and neck radiation therapy

- Symptomatic peripheral neuropathy > grade 2 by Common Terminology Criteria for Adverse
Events (CTCAE) criteria

- Clinically significant sensorineural hearing impairment which may be worsened via
cisplatin exposure (audiometric abnormalities without corresponding clinical deafness
are not grounds for exclusion)

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to AT13387

- Current use of a prohibited medication; the following medications or non-drug
therapies are prohibited: the concurrent use of all herbal supplements is prohibited
during the study (including, but not limited to, St. John's wort, kava, ephedra [ma
huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or
ginseng)

- History or current evidence/risk of visual loss syndromes, including but not limited
to retinal vein occlusion (RVO), retinal detachment, macular degeneration, or visual
migraine headaches

- History or evidence of cardiovascular risk including any of the following:

- History or evidence of current clinically significant uncontrolled arrhythmias
(exception: patients with controlled atrial fibrillation for > 30 days prior to
randomization are eligible)

- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within 6 months prior to randomization

- History or evidence of current >= class II congestive heart failure as defined by
the New York Heart Association (NYHA) functional classification system

- Treatment-refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
therapy

- Patients with intra-cardiac defibrillators

- Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with
chronic or cleared HBV and HCV infection are eligible); patients with known human
immunodeficiency virus (HIV) infection are eligible if not on antiviral agents and
cluster of differentiation (CD)4 counts are adequate (>= 500)

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Any condition or medical problem in addition to the underlying malignancy and organ
dysfunction which the investigator feels would pose unacceptable risk

- Breastfeeding patients are ineligible