Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma

• ClinicalTrials.gov Identifier: NCT00942877
• Recruitment Status: Active, not recruiting
• First Posted: July 21, 2009
• Results First Posted: April 27, 2021
• Last Update Posted: March 12, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alice Chen, M.D., National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: July 18, 2009
• First Posted Date: July 21, 2009
• Results First Submitted Date: March 2, 2021
• Results First Posted Date: April 27, 2021
• Last Update Posted Date: March 12, 2024
• Actual Study Start Date: July 18, 2009
• Actual Primary Completion Date: September 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 6, 2021)

• Minimal Response Rate in Pediatric Participants With Alveolar Soft Part Sarcoma (ASPS) [ Time Frame: Date treatment initiated to date off study, an average of 16.9 cycles for adult patients and 34.7 cycles for pediatric patients (1 cycle = 28 days) ]
  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.0. A minimal response is defined as a 5% overall response rate (Partial Response (PR) + Complete Response (CR)
• Number of Participants With a Response (Partial Response (PR) + Complete Response (CR)) of AZD2171 in Adult Participants With Alveolar Soft Part Sarcoma (ASPS) [ Time Frame: 2 cycles (e.g., one cycle = 28 days) ]
  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all no-target lesions and normalization of tumor marker level. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
• Number of Participants With a Best Observed Response [ Time Frame: Participants were followed for the duration of treatment, an average of 16.9 cycles for adult patients and 34.7 cycles for pediatric patients (1 cycle = 28 days) ]
  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions and normalization of tumor marker level. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease is at least a 20% increase in the sum of the LD of target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
• Number of Participants With a Best Response [ Time Frame: Date treatment initiated to date off study, an average of 16.9 cycles for adult patients and 34.7 cycles for pediatric patients (1 cycle = 28 days) ]
  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions and normalization of tumor marker level. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease is at least a 20% increase in the sum of the LD of target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

• Original Primary Outcome Measures (submitted: July 18, 2009): To determine the response rate (PR + CR) of AZD2171 in patients with ASPS.

Current Secondary Outcome Measures (submitted: April 6, 2021)

Number of Participants With Serious and Non-serious Adverse Events [ Time Frame: Participants were followed for the duration of treatment, an average of 16.9 cycles for adult patients and 34.7 cycles for pediatric patients (1 cycle = 28 days) ]

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma
• Official Title: Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma

Brief Summary

Background:

• Alveolar soft part sarcoma is a type of cancer that develops in tissues that connect, support, or surround other organs in the body. It relies heavily on new blood vessels to grow and spread through the body. There is no effective systemic treatment for patients with alveolar soft part sarcoma.
• The drug AZD2171 (cediranib) is an experimental drug, not yet approved by the Food and Drug Administration. The drug blocks the creation of new blood vessels. The drug has had initial clinical trials, and researchers are interested in determining whether cediranib is effective in inhibiting tumor growth in individuals who have alveolar soft part sarcoma.

Objectives:

- To find out whether AZD2171 works in patients who have alveolar soft part sarcoma.

Eligibility:

- Individuals 18 years of age and older who have been diagnosed with alveolar soft part sarcoma.

Design:

• After an initial screening visit, patients will take AZD2171 by mouth once a day, every day for the duration of the study. The treatment will be given in 28-day cycles.
• Patients will keep a study diary to record the doses taken, any missed doses, and any side effects.
• Patients will have the following tests and procedures during the treatment period: clinic visit with physical examination every 2 weeks during cycles 1 and 2, then at the start of each subsequent cycle, regular blood pressure monitoring, blood and urine tests, heart function tests, imagining scans to evaluate tumor size and response to the treatment, and possible tumor biopsy.

Detailed Description

Background:

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor accounting for less than 1% of soft tissue sarcomas. There is no effective systemic treatment for patients with metastatic ASPS. Little is known with regards to relevant molecular markers as potential therapeutic targets. Cediranib (AZD2171), a vascular endothelial growth factor (VEGF)/KIT tyrosine kinase inhibitor, has recently demonstrated antitumor activity in early phase clinical trials, which included 7 adult and 3 pediatric patients with ASPS.

Objectives:

Adult patients:

• To determine the response rate (Partial Response (PR) + Complete Response (CR)) of AZD2171 in adult patients with ASPS.
• To compare gene expression profiles between pre-treatment and post-treatment biopsy specimens.

Pediatric patients:

-To determine if pediatric patients with ASPS will experience at least a minimal response rate when treated with AZD2171

Eligibility:

Patients must have histologically or cytologically confirmed metastatic alveolar soft part sarcoma.

• Less than 16 years old. Body surface area (BSA) must be greater than or equal to 1.04 m^2 and subject must be able to swallow tablets.
• Adequate organ function.

Design:

Adult patients will be treated with AZD2171 at 30 mg by mouth once a day for 28 days (28-day cycles). Pediatric patients (< 16 years old) will be treated with 12 mg/m^2/day once a day for 28 day (28-day cycles).

Blood pressure will be monitored weekly for the first 2 cycles then every 2 weeks for the remainder of the study (unless patients have experienced elevated blood pressure requiring drug therapy).

Computed tomography (CT) scans will be performed at baseline and every 2 cycles for restaging during the first 18 months; after 18 and 36 months, restaging CT scans will be performed every 3 or 4 cycles, respectively.

The study will be conducted using an optimal two-stage design in both pediatric and adult patients. The portion in adults will rule out an unacceptably low 5% clinical response rate (PR+CR) in favor of a modestly high response rate of 25%. In pediatric patients, the study will rule out an unacceptably low 5% overall clinical response rate (CR + PR) in favor of a higher response rate of 35%.

Optional biopsies will be performed in adult patients only at baseline and after 3-5 days of treatment (Day 3 (D3)-Day 5 (D5)) to evaluate early drug effect. A third optional biopsy after completion of 4 weeks of therapy (between Cycle 1 Day 28 (C1D28) and Cycle 2 Day 7 (C2D7)) may be collected with the intention of providing further information about disease response to treatment. Depending on results of initial gene expression profiles, the timing of the biopsies may be adjusted, but without change in total number of biopsies per patient.

In a retrospective pilot study, CT scans from 20 consecutive off-study patients will be re-reviewed. Response Evaluation Criteria in Solid Tumors (RECIST) imaging measurements will be compared to volumetric density (Total Volume of Viable Tumor, TVVT) CT measurements. The objective is to establish whether volumetric density/percent necrosis algorithms such as TVVT more accurately assess extent of disease and response to therapy than standard RECIST criteria.

The total accrual ceiling is 73 participants (60 adult and 13 pediatric patients).

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sarcoma, Alveolar Soft Part

Intervention

Drug: AZD2171

Cediranib (AZD2171), a vascular endothelial growth factor (VEGF)/KIT tyrosine kinase inhibitor, has demonstrated antitumor activity in early phase clinical trials in adult and pediatric patients with Alveolar Soft Part Sarcoma (ASPS).

Other Name: Cediranib

Study Arms

Experimental: Cediranib (AZD2171) Treatment

Adult participants will be treated with 30 mg by mouth once a day for 28 days (28-day cycles).

Pediatric participants (<16 years old) will be treated with 12 mg/m^2/day once a day for 28 days (28-day cycles).

Intervention: Drug: AZD2171

Publications *

• Cohen JW, Widemann BC, Derdak J, Dombi E, Goodwin A, Dompierre J, Onukwubiri U, Steinberg SM, O'Sullivan Coyne G, Kummar S, Chen AP, Glod J. Cediranib phase-II study in children with metastatic alveolar soft-part sarcoma (ASPS). Pediatr Blood Cancer. 2019 Dec;66(12):e27987. doi: 10.1002/pbc.27987. Epub 2019 Sep 10.
• Hall PE, Shepherd STC, Brown J, Larkin J, Jones R, Ralph C, Hawkins R, Chowdhury S, Boleti E, Bahl A, Fife K, Webb A, Crabb SJ, Geldart T, Hill R, Dunlop J, McLaren D, Ackerman C, Wimalasingham A, Beltran L, Nathan P, Powles T. Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy. Eur Urol Focus. 2020 Sep 15;6(5):999-1005. doi: 10.1016/j.euf.2019.01.010. Epub 2019 Feb 6.
• Powles T, Brown J, Larkin J, Jones R, Ralph C, Hawkins R, Chowdhury S, Boleti E, Bhal A, Fife K, Webb A, Crabb S, Geldart T, Hill R, Dunlop J, Hall PE, McLaren D, Ackerman C, Beltran L, Nathan P. A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK). Ann Oncol. 2016 May;27(5):880-6. doi: 10.1093/annonc/mdw014. Epub 2016 Jan 22.
• Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, Turkbey IB, Lawrence S, Kinders RJ, Choyke P, Simon R, Steinberg SM, Doroshow JH, Helman L. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol. 2013 Jun 20;31(18):2296-302. doi: 10.1200/JCO.2012.47.4288. Epub 2013 Apr 29.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 12, 2017): 53
• Original Enrollment (submitted: July 18, 2009): 27
• Estimated Study Completion Date: December 31, 2024
• Actual Primary Completion Date: September 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

Patients must have histologically confirmed alveolar soft part sarcoma. Pathology should be confirmed at the Laboratory of Pathology, National Institutes of Health.

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 millimeters with conventional techniques or as greater than or equal to 10 millimeters with spiral computed tomography (CT) scan.

Patients must have metastatic alveolar soft part sarcoma that is not curable by surgery. Patients who have surgically resectable tumors with metastasis will be considered on a case by- case basis.

Any prior therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol and the participant must have recovered to eligibility levels from prior toxicity. Patients should be at least 6 weeks out from nitrosoureas and mitomycin C. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the principal investigator's (PI's) discretion, and should haverecovered to eligibility levels from any toxicities.

Any degree of prior treatment is allowed, including other anti-angiogenic treatments (e.g., vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors or bevacizumab). Patients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgery.

Body surface area (BSA) greater than or equal to 1.04 square meter.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 for adults, Karnofsky performance status greater than or equal to 50% for pediatric patients greater than 10 years of age, and Lansky performance status greater than or equal to 50 for pediatric patients less than or equal to 10 years of age.

Life expectancy of greater than 8 weeks.

Patients must have normal organ and marrow function as defined below:

• absolute neutrophil count greater than or equal to 1,500/microliter
• platelets greater than or equal to 100,000/microliter
• total bilirubin less than 1.5 times institutional upper limit of normal
• Aspartate aminotransferase (AST)(Serum glutamic Oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) less than or equal to 2.5 times institutional upper limit of normal
• creatinine within normal limits based on age as follows:

Age (Years) Maximum Serum Creatinine (milligrams per deciliter)

less than or equal to 5 0.8

5 less than age less than or equal to 10 1.0

10 less than age less than or equal to 15 1.2

greater than 15 1.5

OR

creatinine clearance greater than or equal to 60 milliliter/min for adults or greater than or equal to 60 milliliter/min/1.73m^2 for children with creatinine levels above institutional upper limit of normal.

Corrected QT interval (QTc) must be less than 500 msec.

Pediatric patients: Normal left ventricular function with ejection fraction greater than 55% or shortening fraction greater than or equal to 27%.

At present, the potential of Cediranib (AZD2171) for clinically significant drug interactions involving the cytochrome P450 (CYP) isozymes is unknown. However, studies of the agent in rats indicated possible suppression of cytochrome P450, family 1, subfamily A (CYP1A) that may be of biological significance. Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity of pharmacokinetics (PK) of AZD2171 will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications one week prior to starting therapy.

AZD2171 has been shown to terminate fetal development in the rat, as expected for a process dependent on vascular endothelial growth factor (VEGF) signaling. For this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Ability to understand and the willingness to sign a written informed consent document.

Patients should not be receiving any other investigational agents.

Prior therapy with anti-angiogenic agents is permitted.

EXCLUSION CRITERIA:

Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to: active or uncontrolled infection, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.

Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, ibuprofen, pentamidine).

Patients who are unable to swallow tablets.

Mean QTc greater than 500 msec (with Bazett's correction) in screening electrocardiogram or history of familial long Q wave, T wave (QT) syndrome.

Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart.

Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with known abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD2171, breastfeeding should be discontinued if the mother is treated with AZD2171.

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with AZD2171.

Adult patients with hypertension not controlled by medical therapy (hypertension defined as systolic blood pressure greater than 150 millimeters of mercury or diastolic pressure greater than 90 millimeters of mercury despite optimal medical management). Pediatric patients must have blood pressure (BP) within normal limits (WNL) for age. NOTE: blood pressure within the upper limit of normal is defined as: blood pressure less than or equal to the 95th percentile for age, height, and gender, and measured, and not be receiving medication for treatment of hypertension.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 16 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00942877
• Other Study ID Numbers: 090192; 09-C-0192
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: All individual participant data (IPD) will be shared with intramural investigators upon request.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Additionally, requests for all collected individual participant data (IPD) from clinical trials, conducted under a binding collaborative agreement between National Cancer Institute (NCI)/Division of Cancer Treatment and Diagnosis (DCTD) and a pharmaceutical/biotechnology company, that are not under data safety monitoring board (DSMB) monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).

• Current Responsible Party: Alice Chen, M.D., National Cancer Institute (NCI)
• Original Responsible Party: Not Provided
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alice P Chen, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: February 2024