A Randomized Phase II Study of Concurrent Intensity Modulated Radiation Therapy (IMRT), Paclitaxel and Pazopanib (NSC 737754)/Placebo, for the Treatment of Anaplastic Thyroid Cancer
Overview
- Phase
- Phase 2
- Intervention
- Intensity-Modulated Radiation Therapy
- Conditions
- Thyroid Gland Anaplastic Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 123
- Locations
- 130
- Primary Endpoint
- (Phase II) Overall Survival
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This randomized phase II trial studies the side effects and how well intensity-modulated radiation therapy (IMRT) and paclitaxel with or without pazopanib hydrochloride works in treating patients with anaplastic thyroid cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and paclitaxel are more effective when given with pazopanib hydrochloride in treating thyroid cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety of IMRT, paclitaxel, and pazopanib (pazopanib hydrochloride) suspension. (Run-in component) II. To evaluate and compare overall survival at 1 year from study registration. (Phase II component) SECONDARY OBJECTIVES: I. To evaluate local-regional control at 6 and 12 months. (Phase II component) II. To evaluate the rate of grade 4 (Common Terminology Criteria for Adverse Events version 4.0 \[CTCAE, v. 4.0\]) hemorrhage, grade 4 febrile neutropenia, or any grade 5 adverse event assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) III. To evaluate the rates of other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) IV. To evaluate the rate of treatment discontinuation due to toxicity during the induction or concurrent treatment components of the protocol regimen. (Phase II component) V. To evaluate response (as per Response Evaluation Criteria in Solid Tumors \[RECIST\]) of the primary site following the treatment component in subjects with measurable disease prior to chemoradiation. (Phase II component) OUTLINE: RUN-IN COMPONENT: Patients receive paclitaxel intravenously (IV) over 1 hour once weekly and pazopanib hydrochloride orally (PO) once daily (QD) for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and intensity-modulated radiotherapy (IMRT) 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease). RANDOMIZED PHASE II COMPONENT: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease). ARM II: Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease). After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a diagnosis that is noted to be "consistent with anaplastic thyroid cancer" with the presence of a thyroid mass is acceptable)
- •Note: Tissue collection for central review is mandatory, but central review is not required for eligibility; due to the aggressiveness of this disease, treatment will be started prior to central review
- •If there was a total or partial thyroidectomy completed within 3 months of enrollment, the surgical specimen must show the area of anaplastic thyroid cancer to be at least 1 cm in greatest dimension
- •The following minimum diagnostic workup is required:
- •History/physical examination within 2 weeks prior to registration
- •Imaging of neck and brain (computed tomography \[CT\] scan or magnetic resonance imaging \[MRI\]) and chest/abdominal imaging (chest x-ray or chest CT scan, or full body positron emission tomography \[PET\]/CT are acceptable) within 4 weeks prior to registration
- •Note: The CT scan of the neck must be done with contrast or if an MRI is done, with gadolinium; therefore, the CT portion of a full body PET/CT has to be a high resolution CT to be acceptable for eligibility
- •Abdominal imaging must cover the liver and adrenal glands; therefore, separate imaging is not required if these areas are covered by a chest CT scan
- •Electrocardiogram within 10 days prior to registration
- •Zubrod performance status 0-2
Exclusion Criteria
- •Known active invasive malignancy (except for non-melanomatous skin cancer or anaplastic thyroid cancer; the presence of prostate cancer confined to the prostate with a prostate-specific antigen \[PSA\] =\< 1 ng/mL for more than 6 months also is allowed)
- •Prior systemic chemotherapy for anaplastic thyroid cancer
- •Patients who have had chemotherapy or radiotherapy within 4 weeks of registration (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered \> 4 weeks previously
- •Patients receiving other investigational agents
- •Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- •Patients with any of the following cardiovascular conditions within the past 6 months:
- •Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
- •Admission for unstable angina
- •Myocardial Infarction
- •Cardiac angioplasty or stenting
Arms & Interventions
Arm I (paclitaxel, pazopanib hydrochloride, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Intensity-Modulated Radiation Therapy
Arm I (paclitaxel, pazopanib hydrochloride, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Paclitaxel
Arm I (paclitaxel, pazopanib hydrochloride, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Pazopanib Hydrochloride
Arm II (paclitaxel, placebo, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Intensity-Modulated Radiation Therapy
Arm II (paclitaxel, placebo, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Paclitaxel
Arm II (paclitaxel, placebo, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).
Intervention: Placebo Administration
Outcomes
Primary Outcomes
(Phase II) Overall Survival
Time Frame: From randomization to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years.
Overall survival time is defined as time from randomization to the date of death (failure) from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after all eligible participants were potentially followed for 3 years.
(Phase I) Number of Participants With Treatment-related Grade 4 Hemorrhage, Grade 4 Febrile Neutropenia, or Grade 5 Adverse Event (AE), or Discontinuation of Treatment Due to Toxicity [Adverse Events of Concern (AEC)]
Time Frame: From registration to last follow-up. Maximum follow-up for run-in and phase II participants at time of analysis was 7.4 years.
Common Terminology Criteria for AEs (version 4.0) grades AE severity from 1=mild to 5=death. Discontinuation of treatment due to toxicity is defined as \< 75% of planned radiation therapy delivered. "Treatment-related" = definitely, probably, or possibly related to treatment. A single run-in arm was originally planned, but additional run-in arms were added due to amendments to the protocol regimen unrelated to toxicities. A two-stage design based on the binomial distribution was used in which the 1st stage analyzes the run-in arm and the 2nd stage analyzes run-in and phase II pazopanib arm participants combined. Because there were multiple run-in arms, only the last is used in the 2nd stage analysis. 1st stage: If ≤4 of 9 participants experience AEC, then conclude treatment is safe. 2nd stage: If ≤8 of 24 participants experience AEC, then conclude treatment safe. Otherwise conclude the treatment is too toxic. Summary data is provided here, see AE Module for specific AE data.
Secondary Outcomes
- (Phase II) Local-regional Control(From randomization to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years. (Statistical analysis compares full distributions therefore all available follow-up was used.))
- (Phase II) Percentage of Participants With Treatment-related Grade 4 Hemorrhage, Grade 4 Febrile Neutropenia, or Grade 5 Adverse Event, or Discontinuation of Treatment Due to Toxicity [Adverse Events of Concern](From start of treatment to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years.)
- (Phase II) Percentage of Participants With Treatment-related Grade 3 or 4 Adverse Events Other Than Grade 4 Hemorrhage or Grade 4 Febrile Neutropenia [Not Adverse Events of Concern](From start of treatment to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years.)
- (Phase II) Percentage of Participants With Complete or Partial Response of the Primary Site After Chemoradiation Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(2-4 weeks after treatment (approximately week 10-14))