Thyroid Cancer
Conditions
Keywords
radioiodine refractory thyroid cancer, RAD001
Brief summary
Since thyroid cancer becomes refractory to radioactive iodine, treatment options are very limited. Tyrosine kinase inhibitors such as sorafenib have recently shown promise. This trial seeks to expand treatment options for this disease with a new, oral drug called RAD001. It is an inhibitor of the mTOR pathway and has shown activity in neuroendocrine cancers of the gastrointestinal tract and has been approved for the treatment of metastatic renal cell cancer.
Detailed description
* RAD001 will be taken once a day in the morning starting on Day 1 and continue until the participant is no longer participating in the study treatment. * A history and physical exam will be performed the first day of the study and then once a month. Blood tests including coagulation studies, and thyroid studies will be performed monthly. A urine sample will need to be provided on the first day of treatment and then every 2 months. Imaging consisting of a CT or MRI of the neck, chest and abdomen will be done every 8 weeks after starting RAD001. * Participants will remain on this research study for up to 24 months. However, if the participants doctor feels that they are benefiting from the study drug and they do not have severe side effects, they may be given the option to continue taking RAD001.
Interventions
DRUGRAD001
Sponsors
Dana-Farber Cancer Institute
Massachusetts General Hospital
M.D. Anderson Cancer Center
MOUNT SINAI HOSPITAL
Novartis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed locally advanced or metastatic thyroid cancer, excluding thyroid lymphomas not amenable to or refractory to surgical resection, external beam radiotherapy, radioiodine or other local therapies. * Prior therapy with chemotherapy and targeted therapies except for mTor inhibitors is allowed. * Medullary thyroid cancer with documented evidence of disease progression by modified RECIST within 6 months before study day 1 or symptomatic disease at the time of screening in the absence of documented disease progression. * Differentiated thyroid cancer with documented evidence of disease progression by modified RECIST within 6 months before study day 1. * Anaplastic thyroid cancer with disease progression with documented disease progression by modified RECIST within 6 months of study day 1. * Patients must have at least one measurable site of disease according to RECIST criteria that has not previously irradiated. If the patient has has previous radiation to the marker lesion(s), there must be evidence of progression since radiation. * 18 years of age or older * WHO performance status 2 or less * Adequate bone marrow, liver, and renal function * Fasting serum cholesterol 300mg/dL or less OR 7.75 mmol/L or less AND fasting triglycerides 2.5x ULN or less
Exclusion criteria
* Patients receiving anticancer therapies within last 2 weeks or who have received radiation therapy within 3 weeks of study day 1 * Prior therapy with mTOR inhibitors * 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 or patients that may require major surgery during the course of the study * Prior treatment with any investigational drug within the preceding 3 weeks * Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed. * Patients should not receive immunization with attenuated live vaccines within 2 weeks 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 * A known history of HIV seropositivity * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 * 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 * Patients who have received prior treatment wih an mTOR inhibitor * Patients with a known hypersensitivity to RAD001 or other rapamycins or to its excipients * History of noncompliance to medical regimens
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 48 months. | Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 48 months. | The objective response rate is the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. PR or better is achieved if the following are true: Target Lesions: -At least a 30% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target Lesions: No progression. No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Bone Lesions: -\>50% increase in lesions. -No new lesions. |
| Median Overall Survival | Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 5 years post study registration. | Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. |
| Mean Change in Quality of Life [Medullary Thyroid Cancer Population Only] | Measured at baseline and then again at cycle 8 (8 months). | The M. D. Anderson Symptom Inventory (MDASI) questionnaire was used to assess quality of life. Questions 1 to 19 were scored. Each of the 19 questions have a response range of 0 - 10, where 0 represents "not present" and 10 represents "as bad as you can imagine". The 19 responses are averaged together to create a mean score, with a lower score indicating a better quality of life. All questionnaire mean scores at each timepoint are averaged together to give a mean score at that timepoint (baseline and week 8) The mean change in quality of life is calculated by subtracting the baseline mean score from the week 8 mean score. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGlenn Hanna, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
July 2009 to August 2013
Participants by arm
| Arm | Count |
|---|---|
| Arm A RAD001 will be administered orally as once daily dose of 10 mg (one 10mg tablet or two 5mg tablets) continuously from study day 1 until progression of disease or unacceptable toxicity.
RAD001: Taken orally once a day in the morning | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | Arm A |
|---|---|
| Age, Continuous | 63 years |
| ECOG Performance Status 0 - Fully Active | 32 Participants |
| ECOG Performance Status 1 - Restricted | 14 Participants |
| ECOG Performance Status 2- Ambulatory and Capable of Self Care | 4 Participants |
| Previous Therapies External Beam Radiotherapy No | 20 Participants |
| Previous Therapies External Beam Radiotherapy Yes | 30 Participants |
| Previous Therapies Radioactive Iodine No | 19 Participants |
| Previous Therapies Radioactive Iodine Yes | 31 Participants |
| Previous Therapies Surgery No | 6 Participants |
| Previous Therapies Surgery Yes | 44 Participants |
| Previous Therapies Tyrosine Kinase Inhibitors No | 28 Participants |
| Previous Therapies Tyrosine Kinase Inhibitors Yes | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 33 Participants |
| Site of Distant Metastasis Bone No (Not a Metastatic Site) | 29 Participants |
| Site of Distant Metastasis Bone Yes | 21 Participants |
| Site of Distant Metastasis Liver No (Not a Metastatic Site) | 36 Participants |
| Site of Distant Metastasis Liver Yes | 14 Participants |
| Site of Distant Metastasis Lung No (Not a Metastatic Site) | 17 Participants |
| Site of Distant Metastasis Lung Yes | 33 Participants |
| Site of Distant Metastasis Lymph Nodes No (Not a Metastatic Site) | 24 Participants |
| Site of Distant Metastasis Lymph Nodes Yes | 26 Participants |
| Site of Distant Metastasis None No (Not a Metastatic Site) | 49 Participants |
| Site of Distant Metastasis None Yes | 1 Participants |
| Site of Distant Metastasis Other No (Not a Metastatic Site) | 38 Participants |
| Site of Distant Metastasis Other Yes | 12 Participants |
| Subtype Anaplastic | 7 Participants |
| Subtype Differentiated | 33 Participants |
| Subtype Medullary | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 36 / 50 |
Outcome results
Primary
Median Progression Free Survival
Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free.
Time frame: Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 48 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Median Progression Free Survival | 12.5 months |
Comparison: We will declare the trial a success after observing 7 or more patients with PFS within 6 months. The study will have alpha = 0.092 and power =0.970, assuming a 6 month PFS probability of 0.12 for the null and a PFS probability of 0.35 as the alternative hypothesis.
Secondary
Mean Change in Quality of Life [Medullary Thyroid Cancer Population Only]
The M. D. Anderson Symptom Inventory (MDASI) questionnaire was used to assess quality of life. Questions 1 to 19 were scored. Each of the 19 questions have a response range of 0 - 10, where 0 represents not present and 10 represents as bad as you can imagine. The 19 responses are averaged together to create a mean score, with a lower score indicating a better quality of life. All questionnaire mean scores at each timepoint are averaged together to give a mean score at that timepoint (baseline and week 8) The mean change in quality of life is calculated by subtracting the baseline mean score from the week 8 mean score.
Time frame: Measured at baseline and then again at cycle 8 (8 months).
Population: Only 8 of the 10 participants with Medullary Thyroid Cancer filled out both questionnaires (one at baseline and one at cycle 8).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A | Mean Change in Quality of Life [Medullary Thyroid Cancer Population Only] | -0.0621 mean change in score on the MDASI scale | Standard Deviation 0.992 |
Secondary
Median Overall Survival
Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Time frame: Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 5 years post study registration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Median Overall Survival | 32.7 months |
Secondary
Objective Response Rate
The objective response rate is the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. PR or better is achieved if the following are true: Target Lesions: -At least a 30% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target Lesions: No progression. No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Bone Lesions: -\>50% increase in lesions. -No new lesions.
Time frame: Every 2 months for first 24 months, then every 3 months from >24 to 60 months; up to 48 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Objective Response Rate | 6 percentage of participants |