NCT01236547

Intensity-Modulated Radiation Therapy and Paclitaxel With or Without Pazopanib Hydrochloride in Treating Patients With Anaplastic Thyroid Cancer

Completed Phase 2 Results posted Last updated 19 July 2022

What this trial tests

Phase 2 trial testing Intensity-Modulated Radiation Therapy in Thyroid Gland Anaplastic Carcinoma in 123 participants. Completed in 20 May 2022.

Timeline

28 October 2010

Primary endpoint
9 March 2020

20 May 2022

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	123
Start date	28 October 2010
Primary completion	9 March 2020
Estimated completion	20 May 2022
Sites	130 locations across United States

Drugs / interventions tested

• Intensity-Modulated Radiation Therapy
• Paclitaxel — full drug profile →
• Pazopanib Hydrochloride — full drug profile →
• Placebo Administration — full drug profile →

Conditions studied

• Thyroid Gland Anaplastic Carcinoma — all drugs for Thyroid Gland Anaplastic Carcinoma →

Sponsor

National Cancer Institute (NCI)

Who can join

18 and older, any sex, with Thyroid Gland Anaplastic Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

(Phase II) Overall Survival Primary · 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.

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	37.1	21.1 – 53.2
(Phase II) Placebo, Paclitaxel, IMRT	29.0	13.2 – 44.8

(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)] Primary · 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 par

Group	Value	95% CI
(Run-in 1) Pazopanib, Paclitaxel, IMRT	0
(Run-in 2) Pazopanib, Paclitaxil, IMRT	0
(Run-in 3) Pazopanib, Paclitaxel, IMRT	2
(Phase II) Pazopanib, Paclitaxel, IMRT	0

(Phase II) Local-regional Control Secondary · 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.)

Local-regional failure is defined as local-regional relapse/progression in the thyroid bed or regional lymph nodes. Time to local-regional failure is defined as time from randomization to the date of first local-regional recurrence, last known follow-up (censored), or death without local recurrence (competing risk). Failure rates are estimated using the cumulative incidence method. The protocol specifies 6- and 12-month estimates to be reported and for the full distributions of failure times to be compared between the arms. Analysis occurred after all eligible participants were potentially fol

6 months

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	20.0	8.6 – 34.8
(Phase II) Placebo, Paclitaxel, IMRT	27.3	13.3 – 43.3

1 year

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	28.6	14.6 – 44.3
(Phase II) Placebo, Paclitaxel, IMRT	33.6	17.9 – 50.0

(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] Secondary · From start of treatment to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years.

Common Terminology Criteria for Adverse Events (CTCAE, v. 4.0) grades adverse event severity from 1=mild to 5=death. Discontinuation of treatment due to toxicity is defined as \< 75% of planned radiation therapy delivered. Adverse events rated as definitely, probably, or possibly related to treatment were considered treatment-related. Summary data is provided in this outcome measure.; See Adverse Events Module for specific adverse event data.

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	2.8	0.1 – 14.5
(Phase II) Placebo, Paclitaxel, IMRT	11.8	3.3 – 27.5

(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] Secondary · From start of treatment to last follow-up.Maximum follow-up for phase II participants at time of analysis was 4.2 years.

Common Terminology Criteria for Adverse Events (CTCAE, v. 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events rated as definitely, probably, or possibly related to treatment were considered treatment-related. Summary data is provided in this outcome measure.; See Adverse Events Module for specific adverse event data.

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	86.1	70.5 – 95.3
(Phase II) Placebo, Paclitaxel, IMRT	85.3	68.9 – 95.0

(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 Secondary · 2-4 weeks after treatment (approximately week 10-14)

Complete Response: Disappearance of all target lesions; Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Group	Value	95% CI
(Phase II) Pazopanib, Paclitaxel, IMRT	30.4	13.2 – 52.9
(Phase II) Placebo, Paclitaxel, IMRT	33.3	16.5 – 54.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Weekly pre-IMRT and during IMRT, 2 weeks after IMRT, every months for years 1-2, every 6 months for year 3, then annually. Maximum follow-up time was 7.4 years for run-in arms and 4.2 years for phase II arms.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

(Run-in 1) Pazopanib, Paclitaxel, IMRT

Serious: 9/11 (82%)

Deaths: 9/11

(Run-in 2) Pazopanib, Paclitaxil, IMRT

Serious: 6/10 (60%)

Deaths: 10/10

(Run-in 3) Pazopanib, Paclitaxel, IMRT

Serious: 8/11 (73%)

Deaths: 11/11

(Phase II) Pazopanib, Paclitaxel, IMRT

Serious: 28/36 (78%)

Deaths: 31/36

(Phase II) Placebo, Paclitaxel, IMRT

Serious: 22/34 (65%)

Deaths: 30/34

Serious adverse events (88 terms)

Reaction	System	(Run-in 1) Pazopanib, Pacl…	(Run-in 2) Pazopanib, Pacl…	(Run-in 3) Pazopanib, Pacl…	(Phase II) Pazopanib, Pacl…	(Phase II) Placebo, Paclit…
Dysphagia	Gastrointestinal disorders	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Thromboembolic event	Vascular disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Dermatitis radiation	Injury, poisoning and procedural complications	—	—	—	—	—
Confusion	Psychiatric disorders	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Sore throat	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Gastrointestinal disorders - Other	Gastrointestinal disorders	—	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—	—
Fever	General disorders	—	—	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—	—
Metabolism and nutrition disorders - Other	Metabolism and nutrition disorders	—	—	—	—	—
Aspiration	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—

Other adverse events (159 terms — click to expand)

Reaction	System	(Run-in 1) Pazopanib, Pacl…	(Run-in 2) Pazopanib, Pacl…	(Run-in 3) Pazopanib, Pacl…	(Phase II) Pazopanib, Pacl…	(Phase II) Placebo, Paclit…
Dysphagia	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Dermatitis radiation	Injury, poisoning and procedural complications	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
White blood cell decreased	Investigations	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
Hoarseness	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Weight loss	Investigations	—	—	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—	—	—
Skin and subcutaneous tissue disorders - Other	Skin and subcutaneous tissue disorders	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Gastrointestinal disorders - Other	Gastrointestinal disorders	—	—	—	—	—
General disorders and administration site conditions - Other	General disorders	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—

Most-reported serious reactions: Dysphagia, Lymphocyte count decreased, Mucositis oral, Dehydration, Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Thromboembolic event, Nausea, Sepsis.

Data from ClinicalTrials.gov NCT01236547 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.
   Bible KC, Kebebew E, Brierley J, Brito JP, et al · · 2021 · cited 464× · PMID 33728999 · DOI 10.1089/thy.2020.0944
2. Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond.
   Cabanillas ME, Ryder M, Jimenez C. · · 2019 · cited 247× · PMID 31322645 · DOI 10.1210/er.2019-00007
3. Therapeutic advances in anaplastic thyroid cancer: a current perspective.
   Saini S, Tulla K, Maker AV, Burman KD, et al · · 2018 · cited 168× · PMID 30352606 · DOI 10.1186/s12943-018-0903-0
4. Updates on the Management of Thyroid Cancer.
   Araque KA, Gubbi S, Klubo-Gwiezdzinska J. · · 2020 · cited 115× · PMID 32040962 · DOI 10.1055/a-1089-7870
5. Patterns of Treatment Failure in Anaplastic Thyroid Carcinoma.
   Rao SN, Zafereo M, Dadu R, Busaidy NL, et al · · 2017 · cited 111× · PMID 28068873 · DOI 10.1089/thy.2016.0395
6. Anaplastic Thyroid Carcinoma: An Update.
   Jannin A, Escande A, Al Ghuzlan A, Blanchard P, et al · · 2022 · cited 110× · PMID 35205809 · DOI 10.3390/cancers14041061
7. Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options.
   Perri F, Lorenzo GD, Scarpati GD, Buonerba C. · · 2011 · cited 66× · PMID 21611089 · DOI 10.5306/wjco.v2.i3.150
8. Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice.
   Tirrò E, Martorana F, Romano C, Vitale SR, et al · · 2019 · cited 63× · PMID 31540307 · DOI 10.3390/genes10090709