E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with 131I-refractory metastatic or unresectable locally-advanced papillary, follicular, or Hurthle-cell thyroid cancer who are also refractory to, or intolerant of, or have clinical contraindication to, doxorubicin treatment. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055107 |
E.1.2 | Term | Thyroid cancer metastatic |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the objective response rate (ORR) of patients with 131I-refractory metastatic or unresectable locally-advanced papillary, follicular, or Hurthle-cell thyroid cancer who are also refractory to, or intolerant of, or have clinical contraindication to, doxorubicin treatment. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to: - determine the safety profile of AG-013736 - determine the progression-free survival (PFS) - determine the duration of response (DR) - determine overall survival (OS) - obtain blood samples for population pharmacokinetic analyses - obtain blood samples to conduct exploratory studies monitoring circulating endothelial cells as markers of drug response and/or disease - obtain blood samples for UGT1A1 mutation correlation with safety and efficacy - explore patient reported outcomes (PROs) of symptom severity and interference in this study population |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically documented, or 131I-inappropriate metastatic or unresectable locallyadvanced thyroid cancer including papillary, follicular, Hurthle cell, medullary, or anaplastic histologies plus any one of the following: o Failure of 131I to control the disease (documented with radiographic evidence of disease progression defined by RECIST within 12 months prior to enrollment) or 131I is not an appropriate therapy (anaplastic or medullary histology), or lack of iodine uptake by one or more tumors as documented by radioiodine scan. OR o 131I-refractory and failure of doxorubicin (either as a single agent or in combination with other agents) to control the disease, documented with radiographic evidence of disease progression as defined by RECIST criteria and documented with 2 sets of CT/MRI scans (or 2 sets of chest x-rays, bone scans, or x-rays of bone lesion) during doxorubicin therapy or within 12 months after the last dose of doxorubicin
2. If a patient has only locally-advanced cancer without distant metastasis, in addition to satisfying the above inclusion criteria, the disease must also be unresectable (eg, tumor involving vital structure, history of previous surgery in the same area, or concurrent severe medical condition that prevents surgery) AND must be refractory to external beam radiotherapy.
3. At least 1 measurable target lesion, as defined by RECIST. If the only measurable target lesion is located in an externally irradiated field, this lesion may be used as measurable disease only if the lesion diameter has grown by ≥20 % since completion of the prior external irradiation or if the lesion is a new lesion, assuming all other criteria are met.
4. Adequate hepatic, and renal function documented within 14 days prior to treatment as documented by: - AST and ALT ≤2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT ≤5.0 x ULN - total bilirubin ≤1.5 x ULN - serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min - urinary protein <1+ by urine dipstick. If dipstick is ≥1+ then a 24-hour urine collection can be done and the patient may enter only if urinary protein is <2 g per 24 hours
5. Age ≥18 years.
6. ECOG performance status of 0 or 1
7. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤140, and the baseline diastolic blood pressure readings must be ≤90. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
8. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including completion of MDASI.
10. Written and voluntary informed consent. |
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E.4 | Principal exclusion criteria |
1. Thyroid lymphoma
2. Bleeding from lung (as evidenced by hemoptysis) >½ tsp of bright red blood per day within past 1 week
3. Gastrointestinal abnormalities including: - inability to take oral medication - requirement for intravenous alimentation - prior surgical procedures affecting absorption including gastric resection - treatment for active peptic ulcer disease in the past 6 months - active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy. - malabsorption syndromes.
4. Previous treatment with anti-angiogenesis agents including thalidomide, Sutent (SU-011248), AMG 706, sorafenib, and bevacizumab.
5. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine).
6. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John’s wort).
7. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
8. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
9. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, deep vein thrombosis or pulmonary embolism.
10. History of a malignancy (other than thyroid cancer) except those treated with curative intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or those treated with curative intent for any other cancer with no evidence of disease for 5 years.
11. Major surgical procedure within 4 weeks of treatment.
12. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
13. Patients (male and female) having procreative potential who are not using adequate contraception or practicing abstinence.
14. Women who are pregnant or breast-feeding
15. Requirement of anticoagulant therapy except for low-dose anticoagulants for maintenance of patency of central venous access or prevention of deep vein thrombosis
16. History of hemorrhagic or thrombotic cerebro-vascular event in the past 12 months (DVT) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point: Objective Response Rate (ORR), defined as the proportion of patients with confirmed complete response (CR) or confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST), relative to the total population of patients who received at least 1 dose of study medication.
Secondary end points: Progression Free Survival (PFS) defined as the time from start of study treatment to first documentation of objective tumor progression or to death due to any cause, whichever comes first.
Duration of Respons (DR) defined as the time from the first documentation of objective tumor response (unconfirmed complete response or unconfirmed partial response, whichever occurs first) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
Overall survival (OS) defined as the time from the start of study treatment to date of death due to any cause. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient Reported Outcomes |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Definition of the end of the trial is provided in thesection 13 of the protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |