Phase II Study of RAD001 Head and Neck Cancer

November 20, 2017 updated by: Julie E. Bauman, MD, MPH

Phase II Study of RAD001 for Treatment of Refractory, Recurrent, Locally Advanced Squamous Cell Carcinoma of the Head and Neck

To carry out exploratory studies to determine if activity of this regimen correlates with tumor and patient associated markers of the EGF-R/mTOR pathway These markers may correlate with activity of this regimen and provide exploratory insights in to the mechanism of this treatment approach.

Expression of the pathway components including EGF-R and phosphorylated EGF-R (p-EGF-R), ERK and p-ERK, Akt and p-Akt(T308 and S473), p70s6k and p-p70s6k, S6 and p-S6, HIF-1-alpha, p27 and 4E-BP1 will be assessed. Mutation and FISH analysis for EGF-R expression will also be performed on tumor samples. Biopsies will be obtained at the following times: pre-treatment, and after 4 weeks (one cycle) of treatment. If available, original diagnostic tissue may be submitted in place of the pre-treatment biopsy.

Study Overview

Status

Terminated

Intervention / Treatment

Detailed Description

The study of the efficacy of RAD001 will proceed in two stages after the method of Simon . In the first stage 15 patients will be accrued and treated. If 9 or fewer patients show clinical benefit the study will be terminated. If 10 or more patients show clinical benefit the study will proceed to the second stage, accruing an additional 26 patients. If the second stage is complete and a total of 29 or more patients show clinical benefit among the 41 patients treated, the treatment CBR for will be considered high enough to warrant further study. Conversely, if the evaluation of RAD001 concludes at the first stage, or if 28 or fewer patients experience a clinical benefit after completing the second stage, the therapy will not be considered for further study.

Current knowledge about the molecular mechanisms of cancer-related pathways involved in cellular signaling, cell cycle regulation and cell death is yielding therapies directed at specific components of these pathways, such as the epidermal growth factor receptor (EGF-R), the mammalian target of rapamycin (mTOR), the vascular endothelial growth factor receptor (VEGF-R) and the insulin-like growth factor receptor (IFG-R). Both small molecule and monoclonal antibody therapies directed against these targets are available. Furthermore, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and mutation analysis are available for profiling expression of pathway components, raising the possibility of individualized prognosis and therapy.

One receptor in particular, is both a prognostic factor and a therapeutic target in HNSCC. Upregulation of EGF-R expression and aberrant activation of kinase cascades downstream of this receptor occur early in the process of carcinogenesis and play a major role in malignant progression.1 The level of EGF-R expression correlates with recurrence and poor prognosis in HNSCC. A well tolerated anti-EGF-R monoclonal antibody, cetuximab, has shown remarkable activity against HNSCC, including statistically significant improvement in survival for patients with locally advanced disease treated with radiotherapy, leading to its regulatory approval for this disease.2 Unfortunately, despite survival advances achieved with EGF-R inhibitors, the majority (~60%) of patients with advanced disease are refractory to EGF-R directed therapies.3 One anticipated mechanism by which the current regimen may fail in some patients is the upregulation of escape pathways downstream of the EGF-R. A pathway of particular interest is the PI3/AKT/mTOR axis, within which the mTOR protein may be targeted by the tyrosine kinase inhibitor RAD001.

In order to investigate pathway components that may act as an escape mechanism while concurrently targeting a downstream kinase that may enable rescue from resistance to EGF-R directed therapies, we propose this prospective, phase II, single-arm, single-agent interventional clinical trial of RAD001 for patients with refractory SCCHN. The primary outcome is activity of RAD001 while secondary outcomes include safety, toxicity and extensive laboratory correlates to be performed on tumor tissues. By carrying out this clinic-translational trial of the novel mTOR inhibitor, RAD001, in patients with refractory SCCHN, we aim to explore mechanisms of activity of and resistance to inhibitors of the EGF-R pathway components while measuring the clinical activity of RAD001.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • Hillman Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically or cytologically documented squamous cell CA of the head and neck
  • Metastatic and/or recurrent head and neck cancer (not eligible for curative intent surgical or radiation therapy)
  • Patients must have at least one measurable site of disease according to RECIST criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
  • Performance status 0-2
  • Age ≥18 years
  • Non-pregnant
  • Prior treatment:
  • Prior treatment for recurrent or metastatic disease required (at least one): up to but no more than 2 regimens (chemotherapy and/or biologic) allowed.
  • Prior induction and concomitant chemoradiotherapy with a curative intent (with or without biologic agents) is allowed
  • No other serious medical or psychiatric disease
  • Required Lab Values:

Granulocytes ≥ 1,500/µl Platelets ≥ 100,000/µl Bilirubin ≤ 1.5 x ULN INR ≥ 1.3 (or < 3 if on anticoagulation) AST or ALT ≤ 2.5 x ULN (< 5 x ULN in patients with liver metastases) Creatinine ≤ ULN or Creatinine Clearance >= 60 mL/min, if creatinine above ULN

  • Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
  • Patients with accessible tumor tissue must agree to a pre-treatment biopsy at screening. If available, original diagnostic tissue may be submitted in place of the pre-treatment biopsy.
  • Signed informed consent

Exclusion Criteria:

  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
  • Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior treatment with any investigational drug within the preceding 4 weeks
  • Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with RAD001. Topical or inhaled corticosteroids are allowed.
  • Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  • Symptomatic congestive heart failure of New York heart Association Class III or IV
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
  • severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air. PFTs as clinically indicated.
  • uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
  • active (acute or chronic) or uncontrolled severe infections
  • liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • A known history of HIV seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients with an active, bleeding diathesis
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001)
  • Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
  • Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
  • Patients unwilling to or unable to comply with the protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Everolimus 10 mg daily

The study of the efficacy of everolimus will proceed in two stages after the method of Simon1. In the first stage 15 patients will be accrued and treated. If 9 or fewer patients show clinical benefit the study will be terminated. If 10 or more patients show clinical benefit the study will proceed to the second stage, accruing an additional 26 patients. If the second stage is complete and a total of 29 or more patients show clinical benefit among the 41 patients treated, the treatment CBR for will be considered high enough to warrant further study. Conversely, if the evaluation of everolimus concludes at the first stage, or if 28 or fewer patients experience a clinical benefit after completing the second stage, the therapy will not be considered for further study.

1

RAD001 is a pill that will be taken orally (by mouth), at a dose of 10 mg, once a day for 28 days.
Other Names:
  • Everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Benefit Rate (CBR)
Time Frame: Up to 60 months
The number of patients with recurrent/refractory SCCHN (head and neck squamous cell carcinoma) treated with single-agent everolimus that, experience a Complete Response (CR) + number of patients that experience a Partial Response (PR ) + number of patients that experience Stable Disease (SD) / total evaluable patients.
Up to 60 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: Up to 60 months
Up to 60 months
Overall Survival (OS)
Time Frame: Up to 60 months
Up to 60 months
Objective Response Rate (ORR)
Time Frame: Up to 60 months
The number of patients with recurrent/refractory SCCHN (head and neck squamous cell carcinoma) treated with single-agent everolimus that, experience a Complete Response (CR) + number of patients that experience a Partial Response (PR ) / total evaluable patients.
Up to 60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2010

Primary Completion (Actual)

April 26, 2011

Study Completion (Actual)

August 5, 2016

Study Registration Dates

First Submitted

January 18, 2010

First Submitted That Met QC Criteria

January 18, 2010

First Posted (Estimate)

January 20, 2010

Study Record Updates

Last Update Posted (Actual)

December 19, 2017

Last Update Submitted That Met QC Criteria

November 20, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Squamous Cell Carcinoma of the Head and Neck

Clinical Trials on Everolimus 10mg daily

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