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Pembrolizumab & Cabozantinib in Patients With Head and Neck Squamous Cell Cancer Who Have Failed Platinum Based Therapy

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ClinicalTrials.gov Identifier: NCT03468218
Recruitment Status : Recruiting
First Posted : March 16, 2018
Last Update Posted : September 25, 2018
Sponsor:
Collaborator:
Exelixis
Information provided by (Responsible Party):
Nabil F. Saba, Emory University

Brief Summary:
This phase II trial studies how well pembrolizumab and cabozantinib in treating patients with head and neck squamous cell cancer that has come back or spread to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of the pathways needed for cell growth. Giving pembrolizumab and cabozantinib may improve the chances of tumor response in patients with head and neck squamous cell cancer.

Condition or disease Intervention/treatment Phase
Metastatic Head and Neck Carcinoma Paranasal Sinus Squamous Cell Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma Recurrent Hypopharyngeal Squamous Cell Carcinoma Recurrent Laryngeal Squamous Cell Carcinoma Recurrent Oral Cavity Squamous Cell Carcinoma Recurrent Oropharyngeal Squamous Cell Carcinoma Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IV Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IV Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7 Unresectable Head and Neck Squamous Cell Carcinoma Drug: Cabozantinib Biological: Pembrolizumab Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

To estimate the overall response rate (ORR) of patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN) who receive the combination of pembrolizumab and cabozantinib.

SECONDARY OBJECTIVES:

  • To estimate the progression-free survival (PFS) of patients treated with the combination of pembrolizumab and cabozantinib.
  • To identify potential biomarkers related to response to the combination of pembrolizumab and cabozantinib in patients with RM SCCHN.
  • To evaluate whether markers of angiogenesis, Met or pMet expression, or inflammatory activation can predict response to the combination or PFS.
  • To gather exploratory clinical data on a potentially predictive set of biomarkers (potential biomarkers include MET expression by fluorescence in situ hybridization [FISH], next generation sequencing [NGS] and immunohistochemistry [IHC]/immunofluorescence [IHF] of MET proto-oncogene (cMET), phosphorylated cMET (pMET), hepatocyte growth factor (HGF), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3) and heregulin messenger ribonucleic acid [mRNA] level).
  • To further define the toxicities associated with these regimens in patients with SCCHN.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and cabozantinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 2 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Pembrolizumab and Cabozantinib in Patients With RM SCCHN Who Have Failed Platinum Based Therapy
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, cabozantinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and cabozantinib PO QD on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib
Given PO
Other Names:
  • Cabometyx
  • Cometriq

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 2 years after treatment start ]
    Will assess the proportion of subjects with partial response or complete response as defined by Response Evaluation Criteria in Solid Tumors version 1.1 response criteria. ORR will be calculated with 95% confidence interval by binomial distribution. The ability of biomarkers to predict ORR will be estimated by chi-square test and/or logistic regression model.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Duration from date of treatment start to the date of objectively documented progression or death due to any cause, whichever status is recorded first, assessed up to 2 years ]
    The median PFS will be estimated by Kaplan-Meier method along with 95% confidence interval. The biomarker association with PFS will be assessed by the Kaplan-Meier method, log-rank test, and Cox model.



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

Inclusion Criteria:

  • The subject has a histologic or cytologic diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx; squamous cell carcinoma of unknown primary in cervical lymph node can be included only if human papillomavirus (HPV) status is positive
  • Patients must have refractory, recurrent or metastatic disease, which is deemed to be inoperable
  • Patients must have failed platinum based therapy as well as cetuximab; if patients were found to be intolerant of standard first line systemic chemotherapy, patients are eligible to enroll to this study provided both cetuximab and cisplatin were administered prior to enrollment
  • Disease progression must be documented following platinum based chemotherapy; this can be in the recurrent or metastatic setting following platinum or in the concurrent setting provided progression has occurred within 6 months from the last dose of platinum
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator
  • A maximum of one prior radiotherapy regimen, curative or palliative, to the head and neck is allowed; if the radiation is combined with chemotherapy and/or cetuximab, a minimum of 4 months must elapse between the end of radiotherapy and registration; if the radiation is given alone, a minimum of 8 weeks must elapse between the end of radiotherapy and registration; a minimum of 3 weeks must elapse between prior radiation to other areas and registration; treatment areas should be healed with no sequelae from radiation therapy (RT) that would predispose to fistula formation
  • The subject has had an assessment of all known disease sites eg, by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib
  • Life expectancy of greater than 3 months
  • The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Recovery to baseline or ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
  • Within 7 days before the first dose of cabozantinib: The absolute neutrophil count (ANC) ≥ 1000/mm³ without colony stimulating factor support
  • Within 7 days before the first dose of cabozantinib: Platelets ≥ 100,000/mm³
  • Within 7 days before the first dose of cabozantinib: Hemoglobin ≥ 9 g/dL
  • Within 7 days before the first dose of cabozantinib: Bilirubin ≤ 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL
  • Within 7 days before the first dose of cabozantinib: Serum albumin ≥ 2.8 g/dl
  • Within 7 days before the first dose of cabozantinib: Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used
  • Within 7 days before the first dose of cabozantinib: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN
  • Within 7 days before the first dose of cabozantinib: Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
  • Within 7 days before the first dose of cabozantinib: Urine protein/creatinine ratio (UPCR) ≤ 1
  • Within 7 days before the first dose of cabozantinib: Serum phosphorus, calcium, magnesium and potassium ≥ lower limit of normal (LLN)
  • The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
  • Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
  • Female subjects of childbearing potential must not be pregnant at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy); however, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons

Exclusion Criteria:

  • Patients who have HPV negative squamous cell carcinoma of unknown primary in cervical lymph node
  • The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 4 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
  • Prior treatment with cabozantinib or pembrolizumab
  • Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment; systemic treatment with radionuclides within 6 weeks before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
  • Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment
  • The subject has received any other type of investigational agent within 28 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
  • The subject has prothrombin time (PT)/institutional normalized ratio (INR) or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
  • Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel)

    • Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
  • The subject has experienced any of the following:

    • Clinically-significant GI bleeding within 6 months before the first dose of study treatment
    • Hemoptysis of ≥ 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment
    • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  • The subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor invading or encasing any major blood vessels
  • The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
  • The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders including:

      • Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening;
      • Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment;
      • Any history of congenital long QT syndrome;
      • Any of the following within 6 months before the first dose of study treatment:

        • Unstable angina pectoris;
        • Clinically-significant cardiac arrhythmias;
        • Stroke (including transient ischemic attack (TIA), or other ischemic event);
        • Myocardial infarction;
    • GI disorders particularly those associated with a high risk of perforation or fistula formation including:

      • Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
      • Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization

        • Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization. Also no pre-existing fistula of head and neck area; no pre-existing osteonecrosis of jaw (ONJ)
    • Other clinically significant disorders that would preclude safe study participation
  • Major surgery within 12 weeks before the first dose of study treatment; complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment; minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior surgery are not eligible
  • Corrected QT interval by Fridericia's formula (QTcF) > 500 msec within 1 month before the first dose of study treatment

    • Three electrocardiography (ECG)s must be performed for eligibility determination; if the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard
  • Pregnant or lactating females
  • Inability to swallow intact tablets or inability to take pembrolizumab or cabozantinib
  • Previously identified allergy or hypersensitivity to components of the study treatment formulations
  • Patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 1 year post diagnosis; patients with a prior history of squamous cell or basal carcinoma of the skin or in situ cervical cancer must have been curatively treated

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): NCT03468218


Contacts
Contact: Nabil F. Saba, MD 404-778-4995 nfsaba@emory.edu

Locations
United States, Georgia
Emory University Hospital Midtown Recruiting
Atlanta, Georgia, United States, 30308
Contact: Rebecca Holman    404-686-2553    rebecca.b.holman@emory.edu   
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shantina Walls    404-778-4995    shantina.n.walls@emory.edu   
Sponsors and Collaborators
Emory University
Exelixis
Investigators
Principal Investigator: Nabil F. Saba, MD Emory University

Responsible Party: Nabil F. Saba, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT03468218     History of Changes
Other Study ID Numbers: IRB00100269
NCI-2017-02419 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Winship4234-17 ( Other Identifier: Winship Cancer Institute )
First Posted: March 16, 2018    Key Record Dates
Last Update Posted: September 25, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: 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
Pembrolizumab
Antineoplastic Agents