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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

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ClinicalTrials.gov Identifier: NCT03389477
Recruitment Status : Recruiting
First Posted : January 3, 2018
Last Update Posted : May 1, 2018
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma Drug: Palbociclib Drug: Cetuximab Drug: Cisplatin Radiation: Intensity-Modulated Radiation Therapy Procedure: Tumor biopsy Procedure: Peripheral blood draw Other: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 27, 2018
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2026

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Cohort 1: 1: palbociclib, 2: Cisplatin & IMRT, 3: palbociclib
  • 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
Palbociclib is an oral drug available as capsules (or as liquid suspension). The capsules should be taken with food
Other Names:
  • Ibrance
  • PD 0332991
Drug: Cisplatin
-Patients will receive cisplatin via intravenous (IV) infusion over 60 minutes.
Other Names:
  • Platinol-AQ
  • Platinol
Radiation: Intensity-Modulated Radiation Therapy
-Once daily fractions Monday through Friday, with one additional fraction of RT administered on (preferably) Fridays
Other Name: IMRT
Procedure: Tumor biopsy
Tumor tissue will be collected at baseline and then after two cycles of neoadjuvant palbociclib monotherapy
Procedure: Peripheral blood draw
Baseline
Other: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
-Baseline, Step One Cycle 2 Day 22, Day 1 of RT, Day 36 of RT, Cycle 1 Day 1 (adjuvant), Cycle 4 Day 1 (adjuvant), EOT (adjuvant), 8 months after completion of chemoradiation therapy (CRT), 12 months after completion of CRT, 18 months after completion of CRT, 24 months after completion of CRT, 30 months after completion of CRT, 36 months after completion of CRT, 42 months after completion of CRT, 48 months after completion of CRT, 54 months after completion of CRT, 60 months after completion of CRT
Experimental: Cohort 1: 1: palbociclib, 2: Cetuximab & IMRT, 3: palbociclib
  • 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
Palbociclib is an oral drug available as capsules (or as liquid suspension). The capsules should be taken with food
Other Names:
  • Ibrance
  • PD 0332991
Drug: Cetuximab
-Cetuximab must not be administered as an IV push or bolus
Other Name: Erbitux
Radiation: Intensity-Modulated Radiation Therapy
-Once daily fractions Monday through Friday, with one additional fraction of RT administered on (preferably) Fridays
Other Name: IMRT
Procedure: Tumor biopsy
Tumor tissue will be collected at baseline and then after two cycles of neoadjuvant palbociclib monotherapy
Procedure: Peripheral blood draw
Baseline
Other: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
-Baseline, Step One Cycle 2 Day 22, Day 1 of RT, Day 36 of RT, Cycle 1 Day 1 (adjuvant), Cycle 4 Day 1 (adjuvant), EOT (adjuvant), 8 months after completion of chemoradiation therapy (CRT), 12 months after completion of CRT, 18 months after completion of CRT, 24 months after completion of CRT, 30 months after completion of CRT, 36 months after completion of CRT, 42 months after completion of CRT, 48 months after completion of CRT, 54 months after completion of CRT, 60 months after completion of CRT



Primary Outcome Measures :
  1. Tumor response rate of newly diagnosed p16INK4a negative, HPV-unrelated HNSCC to neoadjuvant palbociclib monotherapy [ Time Frame: 2 cycles (56 days) ]
    • 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.


Secondary Outcome Measures :
  1. Combined local-regional disease relapse risk and distant metastases risk following completion of CRT [ Time Frame: Through 18 months after completion of step 2 ]
    • 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.

  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 [ Time Frame: Through 5 years after completion of step 2 ]
    -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.

  3. Progression-free survival (PFS) of patients treated with the three step sequence of palbociclib monotherapy, CRT, and adjuvant palbociclib monotherapy [ Time Frame: Through 2 years after completion of step 2 ]
    -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

  4. Median overall survival (OS) of patients treated with the three step sequence of palbociclib monotherapy, CRT, and adjuvant palbociclib monotherapy [ Time Frame: Through 5 years after completion of step 2 ]
    -Overall survival (OS), defined as the days from the time of diagnosis to death from any cause or the end of follow-up

  5. Overall survival of patients treated with the three step sequence of palbociclib monotherapy, CRT, and adjuvant palbociclib monotherapy [ Time Frame: Through 2 years after completion of step 2 ]
    -Overall survival (OS), defined as the days from the time of diagnosis to death from any cause or the end of follow-up



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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 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)
    • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03389477


Contacts
Contact: Douglas R Adkins, M.D. (314) 362-4471 dadkins@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Douglas R Adkins, M.D.    314-362-4471    dadkins@wustl.edu   
Principal Investigator: Douglas R Adkins, M.D.         
Sub-Investigator: Olivia Aranha, M.D.         
Sub-Investigator: Mackenzie Daly, M.D.         
Sub-Investigator: Hiram Gay, M.D.         
Sub-Investigator: Ryan Jackson, M.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Randal Paniello, M.D.         
Sub-Investigator: Patrik Pipkorn, M.D.         
Sub-Investigator: Jason Rich, M.D.         
Sub-Investigator: Wade Thorstad, M.D.         
Sub-Investigator: Jose Zevallos, M.D., MPH         
Sponsors and Collaborators
Washington University School of Medicine
Pfizer
Investigators
Principal Investigator: Douglas R Adkins, M.D. Washington University School of Medicine

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03389477     History of Changes
Other Study ID Numbers: 201802162
First Posted: January 3, 2018    Key Record Dates
Last Update Posted: May 1, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Palbociclib
Cisplatin
Cetuximab
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action