Phase II Study of RAD001 Head and Neck Cancer

• Sponsor: Julie E. Bauman, MD, MPH (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01051791
• Collaborator: Novartis (Industry)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 79.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: Everolimus 10mg daily	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of RAD001 for Treatment of Refractory, Recurrent, Locally Advanced Squamous Cell Carcinoma of the Head and Neck
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Apr 26, 2011
• Actual Study Completion Date: Aug 5, 2016

Arms and Interventions

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

Drug: Everolimus 10mg daily; 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

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) [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.

Secondary Outcome Measures

1. Progression Free Survival (PFS) [Up to 60 months]

2. Overall Survival (OS) [Up to 60 months]

3. Objective Response Rate (ORR) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Julie E. Bauman, MD, MPH
• Novartis

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Julie E. Bauman, MD, MPH, Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01051791
• Other Study ID Numbers: 08-032
• First Posted: Jan 20, 2010
• Last Update Posted: Dec 19, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Julie E. Bauman, MD, MPH, Professor, University of Pittsburgh: RAD001; Everolimus
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Everolimus

Study Results

Participant Flow

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with a planned treatment of continuous 28-day cycles of everolimus 10 mg by mouth daily.
Period Title: Overall Study
STARTED	13
COMPLETED	9
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with a planned treatment of continuous 28-day cycles of everolimus 10 mg by mouth daily.
Overall Participants	9
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	4 44.4%
Male	5 55.6%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR)
Description	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.
Time Frame	Up to 60 months

Outcome Measure Data

Analysis Population Description

Patients that completed at least 1 cycle of everolimus treatment.

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients that completed at least 1 cycle of everolimus everolimus 10 mg by mouth daily. Response to treatment was evaluated by cross-sectional imaging every 8 weeks or as clinically indicated, starting at the end of cycle 2 and continuing until determination of progressive disease.
Measure Participants	7
Number [percentage of participants]	28 311.1%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Time Frame	Up to 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with a planned treatment of continuous 28-day cycles of everolimus 10 mg by mouth daily.
Measure Participants	9
Median (Full Range) [months]	1.5

3. Secondary Outcome

Title	Overall Survival (OS)
Time Frame	Up to 60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with a planned treatment of continuous 28-day cycles of everolimus 10 mg by mouth daily.
Measure Participants	9
Median (Full Range) [months]	4.5

4. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	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.
Time Frame	Up to 60 months

Outcome Measure Data

Analysis Population Description

Patients that completed at least 1 cycle of everolimus treatment. Response to treatment was evaluated by cross-sectional imaging every 8 weeks or as clinically indicated, starting at the end of cycle 2 and continuing until determination of progressive disease.

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with a planned treatment of continuous 28-day cycles of everolimus 10 mg by mouth daily.
Measure Participants	7
Number [percentage of participants]	0 0%

Adverse Events

Arm/Group Title	Everolimus 10 mg Daily
Arm/Group Description	Patients with any treatment of everolimus 10 mg by mouth daily.
All Cause Mortality
	Everolimus 10 mg Daily
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Everolimus 10 mg Daily
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Everolimus 10 mg Daily
	Affected / at Risk (%)	# Events
Total	8/9 (88.9%)
Blood and lymphatic system disorders
Hemoglobin	7/9 (77.8%)
Leukocytes (total WBC)	3/9 (33.3%)
Lymphopenia	5/9 (55.6%)
Platelets	3/9 (33.3%)
Edema: head and neck	4/9 (44.4%)
Cardiac disorders
Hypotension	1/9 (11.1%)
Gastrointestinal disorders
Anorexia	1/9 (11.1%)
Constipation	3/9 (33.3%)
Dehydration	1/9 (11.1%)
Dry mouth/salivary gland (xerostomia)	2/9 (22.2%)
Dysphagia (difficulty swallowing)	5/9 (55.6%)
Mucositis/stomatitis (functional/symptomatic), Oral cavity	3/9 (33.3%)
Nausea	2/9 (22.2%)
Salivary gland changes/saliva	1/9 (11.1%)
Vomiting	2/9 (22.2%)
General disorders
Fatigue (asthenia, lethargy, malaise)	5/9 (55.6%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/9 (22.2%)
Odor (patient odor)	1/9 (11.1%)
Rigors/chills	1/9 (11.1%)
Pain - Other (Specify, __)	3/9 (33.3%)
Pain, Abdomen NOS	2/9 (22.2%)
Pain, External ear	1/9 (11.1%)
Pain, Extremity-limb	2/9 (22.2%)
Pain, Eye	1/9 (11.1%)
Pain, Face	2/9 (22.2%)
Pain, Head/headache	3/9 (33.3%)
Pain, Joint	1/9 (11.1%)
Pain, Middle ear	1/9 (11.1%)
Pain, Oral cavity	2/9 (22.2%)
Pain, Throat/pharynx/larynx	2/9 (22.2%)
Infections and infestations
Infection - Other (Specify, __)	2/9 (22.2%)
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	3/9 (33.3%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	5/9 (55.6%)
Albumin, serum-low (hypoalbuminemia)	6/9 (66.7%)
Alkaline phosphatase	2/9 (22.2%)
Calcium, serum-low (hypocalcemia)	2/9 (22.2%)
Cholesterol, serum-high (hypercholesteremia)	1/9 (11.1%)
Glucose, serum-high (hyperglycemia)	7/9 (77.8%)
Glucose, serum-low (hypoglycemia)	1/9 (11.1%)
Phosphate, serum-low (hypophosphatemia)	1/9 (11.1%)
Potassium, serum-low (hypokalemia)	4/9 (44.4%)
Sodium, serum-low (hyponatremia)	3/9 (33.3%)
Musculoskeletal and connective tissue disorders
Fibrosis-deep connective tissue	1/9 (11.1%)
Muscle weakness, generalized or specific area (not due to neuropathy), Facial	1/9 (11.1%)
Trismus (difficulty, restriction or pain when opening mouth)	1/9 (11.1%)
Nervous system disorders
Dizziness	1/9 (11.1%)
Neuropathy: cranial, CN IX Motor-pharynx; Sensory-ear, pharynx, tongue	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/9 (11.1%)
Bronchospasm, wheezing	2/9 (22.2%)
Cough	2/9 (22.2%)
Dyspnea (shortness of breath)	1/9 (11.1%)
Obstruction/stenosis of airway, Trachea	1/9 (11.1%)
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	1/9 (11.1%)
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify, __)	2/9 (22.2%)
Dry skin	2/9 (22.2%)
Pruritus/itching	3/9 (33.3%)
Rash/desquamation	2/9 (22.2%)
Rash: acne/acneiform	2/9 (22.2%)
Skin breakdown/decubitus ulcer	2/9 (22.2%)
Ulceration	2/9 (22.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.