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. |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055107 |
E.1.2 | Term | Thyroid cancer metastatic |
|
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. |
|
E.2.2 | Secondary objectives of the trial |
ユ determine the safety profile of AG-013736
ユ determine the progression-free survival (PFS)
ユ determine the duration of response (DR)
ユ determine overall survival (OS)
ユ obtain blood samples for population pharmacokinetic analyses
ユ obtain blood samples to conduct exploratory studies monitoring circulating endothelial cells as markers of drug response and/or disease
ユ obtain blood samples for UGT1A1 mutation correlation with safety and efficacy
ユ explore patient reported outcomes (PROs) of symptom severity and interference in this
study population |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Histologically documented, 131I-refractory metastatic or unresectable locally-advanced thyroid cancer of papillary, follicular or Hurthle cell histology plus any one of the
following:
- 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 6 months after the last dose of doxorubicin (scans or x-rays must be received and verified by imaging core laboratory before patient can receive treatment);
- Intolerance of doxorubicin therapy, defined as occurrence of life-threatening or grade 4 toxicity attributable to previous therapy with doxorubicin and have at least one measurable target lesion unirradiated by external beam radiation (a maximum of 10 patients will be eligible under this criteria); or
- Doxorubicin therapy is clinically contraindicated, defined as patients who have
received a cumulative doxorubicin dose of >450 mg/m2 during previous therapy.
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 (CT/MRI scans must be received and verified by imaging core laboratory before patient
can receive treatment). Baseline scans must be received by the imaging core laboratory before the patient can receive treatment with AG-013736.
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 (see Appendix D)
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. |
|
E.4 | Principal exclusion criteria |
1. Central lung lesions involving major blood vessels (arteries or veins). (Central lesions that
maintain the structural integrity of vessels have the potential to bleed if the tumor lesion undergoes necrosis. MRI or CT angiography should be used in any case where there is any question as to whether blood vessels are involved.)
2. Thyroid lymphoma or anaplastic or medullary histology
3. Bleeding from lung (as evidenced by hemoptysis) > 1/2 tsp of bright red blood per day within past 1 week
4. Gastrointestinal abnormalities including:
ユ inability to take oral medication
ユ requirement for intravenous alimentation
ユ prior surgical procedures affecting absorption including gastric resection
ユ treatment for active peptic ulcer disease in the past 6 months
ユ 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.
ユ malabsorption syndromes.
5. Previous treatment with anti-angiogenesis agents including thalidomide, Sutent (SU-011248), AMG 706, sorafenib, and bevacizumab.
6. 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).
7. 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メs wort).
8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
9. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
10. 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.
11. 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
12. Major surgical procedure within 4 weeks of treatment.
13. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
14. Patients (male and female) having procreative potential who are not using adequate contraception or practicing abstinence.
15. Women who are pregnant or breast-feeding |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR) according to RECIST criteria |
|
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 | No |
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 | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
|
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
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 |