Los Tres Paso: Neoadjuvant Palbociclib Monotherapy, Concurrent Chemoradiation Therapy, Adjuvant Palbociclib Monotherapy in Patients With p16INK4a Negative, HPV-Unrelated Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the results of treating patients with HPV-unrelated head and neck squamous cell carcinoma with neoadjuvant single-agent palbociclib, followed by chemoradiation (either cisplatin + IMRT or cetuximab + IMRT depending on patient characteristics), followed by adjuvant single-agent palbociclib.

Official Title
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Los Tres Paso Trial: Step One - Neoadjuvant Palbociclib Monotherapy, Step Two - Concurrent Chemoradiation Therapy, and Step Three - Adjuvant Palbociclib Monotherapy in Patients With p16INK4a Negative, HPV-Unrelated Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Cetuximab
* Drug: Cisplatin
* Radiation: Intensity-Modulated Radiation Therapy
* Procedure: Tumor biopsy
* Procedure: Peripheral blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Larynx SCC, hypopharynx SCC, or oral cavity SCC. HPV-unrelated OPSCC [defined as p16INK4a negative by IHC (staining in < 70% of cells) or HPV High Risk (Type 16 or 18) negative by ISH]. P16INK4a positive larynx SCC, hypopharynx SCC, and oral cavity SCC are eligible given the unknown effect of this on the biology of SCC of these subsites. Overall Stage III, IVA, or IVB disease per AJCC version 7.0 Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. At least 18 years of age. Normal bone marrow function as defined below: Absolute neutrophil count ≥ 1,000/mcL Platelets ≥ 100,000/mcL Hemoglobin ≥ 9.0 g/dL QTc < 500 msec by Fridericia Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 90 days after completion of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Additional Cohort 1 Eligibility Criteria: Patients enrolling to Cohort 1 must meet all of the following criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Adequate organ function defined as: Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN) and creatinine clearance ≥ 75 mL/min Bilirubin ≤ 1.5 x IULN ALT and AST ≤ 2.5 x IULN Additional Cohort 2 Eligibility Criteria: Patients enrolling to Cohort 2 must meet at least one of the following criteria: ECOG performance status of 2 Reduced organ function defined as: Creatinine clearance 30-75 mL/min Bilirubin 1.5-2 x IULN ALT and AST 2.5-5 x IULN Exclusion Criteria: Diagnosis of cutaneous, paranasal sinus, salivary, or nasopharynx SCC, or diagnosis of neck nodes with unknown primary. Diagnosis of P16/HPV-ISH positive OPSCC. Presence of distant metastatic disease. Prior systemic therapy for current diagnosis of HNSCC. A history of other malignancy ≤ 2 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or low risk/curatively treated prostate, thyroid, and cervical cancers. Currently receiving any other investigational agents. Treated within the last 7 days prior to Day 1 of protocol therapy with: Food or drugs that are known to be STRONG CYP3A4 inhibitors (e.g. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, telithromycin, indinavir, ritonavir, nelfinavir, atazanavir, amprenavir, nefazodone, diltiazem, and delavirdine) or inducers (e.g. glucocorticoids, progesterone, rifampin, phenobarbital, St. John's wort) [moderate CYP3A4 inhibitors/inducers are okay] Drugs that are known to prolong the QT interval Drugs that are proton pump inhibitors A history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, cisplatin (for Cohort 1), or cetuximab (for Cohort 2). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (e.g. hypocalcemia, hypokalemia, hypomagnesemia). History of cirrhosis. History of renal or liver transplant. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 28 days of study entry. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Known HIV-positivity and on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with palbociclib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 1: palbociclib, 2: Cisplatin & IMRT, 3: palbociclib<br>Step 1: Neoadjuvant palbociclib monotherapy (125 mg/day, Days 1-21 of a 28-day cycle for two cycles) Step 2: Cisplatin 100 mg/m^2 given on Days 1 and 22 with accelerated IMRT 70 Gy to be administered over 6 weeks Step 3: Adjuvant palbociclib 125 mg/day, days 1-21 of each 28-day cycle for six cycles. Adjuvant palbociclib will begin 16 to 22 weeks following completion of cisplatin & IMRT | Drug: Palbociclib<br>* Palbociclib is an oral drug available as capsules (or as liquid suspension). The capsules should be taken with food<br>* Other names: PD 0332991;Drug: Cisplatin<br>* -Patients will receive cisplatin via intravenous (IV) infusion over 60 minutes.<br>* Other names: Platinol;Radiation: Intensity-Modulated Radiation Therapy<br>* -Once daily fractions Monday through Friday, with one additional fraction of RT administered on (preferably) Fridays<br>* Other names: IMRT;Procedure: Tumor biopsy<br>* Tumor tissue will be collected at baseline and then after two cycles of neoadjuvant palbociclib monotherapy If the patient has been previously enrolled in Washington University's TAP protocol (head and neck bank, HRPO #201102323), tissue that has been banked may be accessed in lieu of fresh biopsy at baseline.<br>Procedure: Peripheral blood draw<br>* Baseline and post-treatment<br>|
| Experimental: Cohort 2: 1: palbociclib, 2: Cetuximab & IMRT, 3: palbociclib<br>Step 1: Neoadjuvant palbociclib monotherapy (125 mg/day, Days 1-21 of a 28-day cycle for two cycles) Step 2: Cetuximab given one week before RT and then weekly with accelerated IMRT 70 Gy to be administered over 6 weeks Step 3: Adjuvant palbociclib 125 mg/day, days 1-21 of each 28-day cycle for six cycles. Adjuvant palbociclib will begin 16 to 22 weeks following completion of cetuximab & IMRT | Drug: Palbociclib<br>* Palbociclib is an oral drug available as capsules (or as liquid suspension). The capsules should be taken with food<br>* Other names: PD 0332991;Drug: Cetuximab<br>* -Cetuximab must not be administered as an IV push or bolus<br>* Other names: Erbitux;Radiation: Intensity-Modulated Radiation Therapy<br>* -Once daily fractions Monday through Friday, with one additional fraction of RT administered on (preferably) Fridays<br>* Other names: IMRT;Procedure: Tumor biopsy<br>* Tumor tissue will be collected at baseline and then after two cycles of neoadjuvant palbociclib monotherapy If the patient has been previously enrolled in Washington University's TAP protocol (head and neck bank, HRPO #201102323), tissue that has been banked may be accessed in lieu of fresh biopsy at baseline.<br>Procedure: Peripheral blood draw<br>* Baseline and post-treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate of Newly Diagnosed p16INK4a Negative, HPV-unrelated HNSCC to Neoadjuvant Palbociclib Monotherapy | Tumor response rate is defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) based on RECIST criteria CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | 2 cycles (56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined Local-regional Disease Relapse Risk and Distant Metastases Risk Following Completion of CRT | Local-regional disease relapse, a binary variable (Yes vs. No). Local-regional disease relapse rate is defined as the proportion of subjects alive who have local-regional progressed disease at 18 months following completion of CRT, stratified by cohorts. Distant metastases, a binary variable (Yes vs. No). Distant metastases rate is defined as the proportion of subjects alive who have distant metastases at 18 months following completion of CRT, stratified by cohorts. | Through 18 months after completion of step 2 | 
| Median Progression-free Survival (PFS) (Stratified by Cohort) of Patients Treated With the Three Step Sequence of Palbociclib Monotherapy, CRT, and Adjuvant Palbociclib Monotherapy | -Progression-free survival (PFS), defined as the interval from the start of Step 2 (CRT) to the first documentation of disease progression or death from any cause or the end of follow-up, stratified by cohorts. | Through 5 years after completion of step 2 | 
| Progression-free Survival (PFS) of Patients Treated With the Three Step Sequence of Palbociclib Monotherapy, CRT, and Adjuvant Palbociclib Monotherapy | -Progression-free survival (PFS), defined as the days from the start of Step 2 (CRT) to the first documentation of disease progression or death from any cause or the end of follow-up | Through 2 years after completion of step 2 | 
| Median Overall Survival (OS) of Patients Treated With the Three Step Sequence of Palbociclib Monotherapy, CRT, and Adjuvant Palbociclib Monotherapy | -Overall survival (OS), defined as the days from the time of diagnosis to death from any cause or the end of follow-up | Through 5 years after completion of step 2 | 
| Overall Survival of Patients Treated With the Three Step Sequence of Palbociclib Monotherapy, CRT, and Adjuvant Palbociclib Monotherapy | -Overall survival (OS), defined as the days from the time of diagnosis to death from any cause or the end of follow-up | Through 2 years after completion of step 2 |