Anaplastic Thyroid Cancer
Conditions
Keywords
thyroid neoplasms, thyroid cancer, thyroid carcinoma
Brief summary
The purpose of the study is to determine the safety and efficacy of combretastatin combined with paclitaxel and carboplatin in the treatment of anaplastic thyroid cancer (ATC).
Detailed description
Anaplastic thyroid carcinoma (ATC) is a high-grade neoplasm, characterized by an aggressive clinical course with brief survival, and refractoriness to currently available local and systemic modalities of treatment. There is no standard therapy for ATC, and no randomized comparative trials have been known to be conducted in this disease. One potential strategy is to combine the anti-tumor activity of the vascular disrupting agent combretastatin with conventional cytotoxic agents. This study will compare the overall survival of ATC patients treated with the triplet combination of combretastatin, paclitaxel, and carboplatin compared with the doublet treatment of paclitaxel and carboplatin.
Interventions
DRUGCA4P
CA4P 60mg/m squared for Days 1, 8, 15 for 6 cycles
DRUGpaclitaxel
200mg/m squared on Day 1
DRUGcarboplatin
6 AUC on Day 1 following paclitaxel
Sponsors
Mateon Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Anaplastic thyroid carcinoma histologically or cytologically confirmed by a pathology review * Refractory to or progressed during or after therapy, or relapsed within 6 months following initial combined modality therapy (usually including systemic chemotherapy and radiation) for regionally advanced disease * Systemic therapy is limited to one chemotherapy regimen that is clearly administered contiguously, (i.e., in an uninterrupted primary therapeutic approach) * Prior radiation: 3 weeks must have elapsed since radiation and disease must be present beyond radiation ports * Minimum of 3 weeks must have elapsed from the time of last chemotherapy prior to the first dose of study drug * Patients with bulky thyroid/neck masses and/or suspicion of airway obstruction must undergo screening (indirect and direct laryngoscopy) to ensure patency of the trachea/airway prior to study enrollment and treatment * ECOG Performance Score less than or equal to 2 * Adequate bone marrow reserve as evidenced by absolute neutrophil count (ANC) greater than 1,500/microL, platelet count greater than 75,000/microL. * Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (less than 177 micromol/L) * Adequate hepatic function as evidenced by serum total bilirubin less than 2X greater than the upper limit of normal (ULN) (less than3X ULN in patients with liver metastases), AST (aspartate aminotransferase)/ALT (alanine aminotransferase) less than or equal to 3X the ULN for the local reference lab (less than or equal to 5X the ULN for patients with liver metastases) * No clinically important sequelae from any prior surgery or radiotherapy.
Exclusion criteria
* Tumors confined to the thyroid. * Clinically evident brain metastasis, including symptomatic involvement, evidence of cerebral edema by CT or MRI, radiographic evidence of progression of brain metastasis since definitive therapy, or continued requirement for corticosteroids * Patients who receive chemotherapy for metastatic disease after completion of a combined modality approach. * History of malignancies other than ATC except curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current PSA of less than 4.0 mg/dL or microg/L * Known hypersensitivity to CA4P, paclitaxel or carboplatin, or any of their components * Receiving concurrent investigational therapy or who have received investigational therapy for any indication within 28 days of the first scheduled day of dosing * Greater than Grade 2 peripheral neuropathy * History of prior cerebrovascular event, including transient ischemic attack * Uncontrolled hypertension (blood pressure greater than 150/100 mm Hg despite medication) * Symptomatic vascular disease (e.g. intermittent claudication) * History of unstable angina pectoris pattern, myocardial infarction (including non-Q wave MI) within the past 6 months, or NYHA Class III and IV congestive heart failure * History of torsade de pointes * Bradycardia (less than 60 b/m), heart block (excluding 1st degree block, being PR interval prolongation only), and congenital long QT syndrome * Any ventricular arrhythmias, or new ST segment elevation or depression or Q wave on ECG * Ejection fractions less than normal (i.e. less than 45%) * QTc prolongation greater than 450 ms * Requirement of any drugs known to prolong the QTc interval, including anti-arrhythmic medications * Potassium concentrations below 4.0 mEq/dL and magnesium concentrations below 1.8 mg/dL despite being on an electrolyte supplement * Requirement of any drugs known to prolong the QTc interval * History of solid organ transplant or bone marrow transplant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall Survival | From randomization to date last known alive |
Secondary
| Measure | Time frame |
|---|---|
| To Determine Progression Free Survival | from randomization through end of study visit |
| To Determine Percentage of 1 Year Survival | from randomization through end of study visit |
Countries
Belarus, Bulgaria, Egypt, India, Israel, Italy, Poland, Romania, Russia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study truncated from 180 to 80 subjects. Subjects were enrolled from August 2007 through March 2010 at 40 worldwide, academic and local-regional clinical sites.
Pre-assignment details
During screening, the diagnosis of anaplastic thyroid cancer was centrally confirmed often leading to enrollment and randomization delays.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1, Active: CA4P + Carboplatin + Paclitaxel Randomized 2:1 to receive six 21-day cycles of CA4P (60mg/m2)on days 1, 8, 15 + carboplatin (AUC 6) + paclitaxel (200 mg/m2) on Day 2. Subjects without progressive disease may continue maintenance CA4P infusions until progressive disease, then followed monthly for survival. | 55 |
| Arm 2, Control: Carboplatin + Paclitaxel On Day 2 of six 21-cycles subjects received Carboplatin (AUC 6) + paclitaxel (200 mg/m2). Subjects without progressive disease were followed monthly for survival. | 25 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Phase | Progressive Disease | 14 | 0 |
| Treatment Phase | Adverse Event | 12 | 5 |
| Treatment Phase | Disease Progression | 12 | 5 |
| Treatment Phase | Other | 6 | 3 |
| Treatment Phase | Physician Decision | 4 | 2 |
| Treatment Phase | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Arm 1, Active: CA4P + Carboplatin + Paclitaxel | Arm 2, Control: Carboplatin + Paclitaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 11 Participants | 37 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 14 Participants | 43 Participants |
| Age, Continuous | 61.5 years STANDARD_DEVIATION 10.72 | 61.2 years STANDARD_DEVIATION 10.54 | 61.4 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment Belarus | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Bulgaria | 3 participants | 0 participants | 3 participants |
| Region of Enrollment India | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Israel | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Italy | 13 participants | 8 participants | 21 participants |
| Region of Enrollment Poland | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Romania | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Russian Federation | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Ukraine | 1 participants | 1 participants | 2 participants |
| Region of Enrollment United Kingdom | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 20 participants | 5 participants | 25 participants |
| Sex: Female, Male Female | 25 Participants | 18 Participants | 43 Participants |
| Sex: Female, Male Male | 30 Participants | 7 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 50 / 51 | 24 / 24 |
| serious Total, serious adverse events | 21 / 51 | 5 / 24 |
Outcome results
Primary
Overall Survival
Time frame: From randomization to date last known alive
Population: All randomized subjects (the Intent-to-treat population) included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1, Active: CA4P + Carboplatin + Paclitaxel | Overall Survival | 5.2 months |
| Arm 2, Comparator: Carboplatin + Paclitaxel | Overall Survival | 4.0 months |
p-value: 0.223Log Rank
Secondary
To Determine Percentage of 1 Year Survival
Time frame: from randomization through end of study visit
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1, Active: CA4P + Carboplatin + Paclitaxel | To Determine Percentage of 1 Year Survival | 26 percentage of participants |
| Arm 2, Comparator: Carboplatin + Paclitaxel | To Determine Percentage of 1 Year Survival | 9 percentage of participants |
Secondary
To Determine Progression Free Survival
Time frame: from randomization through end of study visit