Sunitinib or Cediranib for Alveolar Soft Part Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01391962
First received: July 9, 2011
Last updated: October 15, 2014
Last verified: December 2013
  Purpose

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) and sunitinib (SU011248), oral small molecule inhibitors of VEGF receptor tyrosine kinases, are showing preliminary evidence of activity in patients with ASPS.

Objectives:

  • Part I: Determine the objective response rate (ORR) of single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS.
  • Part II: Determine the ORR of cediranib in patients who progress on the sunitinib arm, and determine the ORR of sunitinib in patients who progress on the cediranib arm.
  • Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib and

single-agent sunitinib malate in patients with advanced ASPS.

Eligibility:

  • Patients aged greater than or equal to 16 years with histologically or cytologically confirmed metastatic ASPS.
  • Patients must show evidence of objective disease progression per RECIST 1 on scans within the 3-month period immediately preceding enrollment. Both scans used to determine disease progression should have been obtained within this 6-month period.
  • Patients with newly diagnosed, unresectable, measurable, metastatic ASPS who show clinical evidence of disease progression will be eligible.
  • Patients must not have received treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with bevacizumab is allowed.

Design:

  • Part I: Patients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, once a day in 28-day cycles.
  • Part II: At the time of disease progression, patients will cross over to the other treatment arm after a 2-week wash-out period.
  • Appropriate anatomic imaging studies will be performed at baseline and every 2 cycles for restaging.
  • The study will be conducted using an optimal two-stage design to rule out an unacceptably low 15% clinical response rate (PR+CR) in favor of a modestly high response rate of 40%.

The study will initially enroll 10 evaluable patients in each arm. If 0 or 1 of the 10 patients has a clinical response, then no further patients will be accrued. If 2 or more the first 10 patients have a response, then accrual continues to a total of 22 patients in each arm.


Condition Intervention Phase
Sarcoma, Alveolar Soft Part
Drug: Cediranib
Drug: Sunitinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial In Which Patients With Metastatic Alveolar Soft Part Sarcoma Are Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at Disease Progression

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the objective response rate (ORR) of single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS. [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Determine the ORR of cediranib in patients who progress on thesunitinib arm, and determine the ORR of sunitinib in patients whoprogress on the cediranib arm [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine the progression-free survival (PFS) at 24 weeks in Part I and in Part II of the study for single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS. [ Time Frame: 4 and 6 months ] [ Designated as safety issue: No ]
  • Perform pharmacokinetic analysis for cediranib [ Time Frame: At the time of progression ] [ Designated as safety issue: No ]

Estimated Enrollment: 70
Study Start Date: June 2011
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part I
Patients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, once a day in 28-day cycles
Drug: Cediranib
30 mg orally, once daily, in 28 day cycles
Drug: Sunitinib
37.5 mg orally, once a day, in 28-day cycles
Experimental: Part II
At the time of disease progression patients will cross over to the other treatment arm after a 2-week wash-out period.
Drug: Cediranib
30 mg orally, once daily, in 28 day cycles
Drug: Sunitinib
37.5 mg orally, once a day, in 28-day cycles

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) and sunitinib (SU011248), oral small molecule inhibitors of VEGF receptor tyrosine kinases, are showing preliminary evidence of activity in patients with ASPS.

Objectives:

  • Part I: Determine the objective response rate (ORR) of single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS.
  • Part II: Determine the ORR of cediranib in patients who progress on the sunitinib arm, and determine the ORR of sunitinib in patients who progress on the cediranib arm.
  • Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib and

single-agent sunitinib malate in patients with advanced ASPS.

Eligibility:

Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be

evaluated and compared to the first 13 patients by the study statistician and the Principal

Investigator. Patients with newly diagnosed ASPS with clinical evidence of disease progression will also be assessed separately.

  • Patients aged greater than or equal to 16 years with histologically or cytologically confirmed metastatic ASPS.
  • Patients must show evidence of objective disease progression per RECIST 1 on scans within the 3-month period immediately preceding enrollment. Both scans used to determine disease progression should have been obtained within this 6-month period.
  • Patients with newly diagnosed, unresectable, measurable, metastatic ASPS who show clinical evidence of disease progression will be eligible.
  • Patients must not have received treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with bevacizumab is allowed.

Design:

  • Part I: Patients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, once a day in 28-day cycles.
  • Part II: At the time of disease progression, patients will cross over to the other treatment arm after a 2-week wash-out period.
  • Appropriate anatomic imaging studies will be performed at baseline and every 2 cycles for restaging.
  • The study will be conducted using an optimal two-stage design to rule out an unacceptably low 15% clinical response rate (PR+CR) in favor of a modestly high response rate of 40%.

The study will initially enroll 10 evaluable patients in each arm. If 0 or 1 of the 10 patients has a clinical response, then no further patients will be accrued. If 2 or more the first 10 patients have a response, then accrual continues to a total of 22 patients in each arm.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be evaluated and compared to the first 13 patients by the study statistician and the Principal Investigator.

  • Patients must have histologically confirmed metastatic alveolar soft part sarcoma that is not curable by surgery. Diagnosis of malignancy must be confirmed by the department of pathology at the institution where the patient is enrolled prior to patient enrollment.
  • Patients must show evidence of objective disease progression per RECIST 1 on scans within the 6 month period immediately preceding enrollment. Both scans used to determine disease progression should have been obtained within this 6-month period.
  • Patients with newly diagnosed, unresectable, metastatic, and measurable ASPS who show clinical evidence of disease progression (including history and increasing physical symptoms) will also be eligible. On-study documentation will include a physician s rationale that supports evidence of clinical disease progression (i.e., increasing tumor pain).
  • 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 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.
  • 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 who have had prior monoclonal antibody therapy must have completed that therapy at least 3 half-lives of the antibody or 6 weeks ago. Patients who have received more than a cumulative dose of 350 mg/m(2) of doxorubicin may be enrolled at the discretion of the Coordinating Center PI after consultation with a cardiologist and if screening echocardiogram is normal.
  • 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 Coordinating Center PI s discretion, and should have recovered to eligibility levels from any toxicities.
  • Patients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgery.
  • Age greater than or equal to 16 years. Patients age 16-17 years are eligible only if they have a BSA greater than or equal to 1.7 m(2) or weigh greater than or equal to 60 kg.
  • ECOG performance status less than or equal to 2.
  • Life expectancy of greater than 3 months.
  • Patients must have normal organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL
    • absolute neutrophil count greater than or equal to 1,500/mcL
    • platelets greater than or equal to 100,000/mcL
    • hemoglobin greater than or equal to 9 g/dL
    • total serum bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal
    • creatinine within normal institutional limits

OR

  • creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels above institutional normal

    • QTc < 480 msec (with Bazett s correction) in screening electrocardiogram.
    • The following groups of patients are eligible after consultation with a cardiologist and at the Coordinating Center PI s discretion, provided they have New York Heart Association Class II (NYHA) cardiac function on baseline ECHO/MUGA:
  • those with a history of Class II heart failure who are asymptomatic on treatment
  • those with prior anthracycline exposure greater than a cumulative dose of 350 mg/m(2)
  • those who have received central thoracic radiation that included the heart in the radiotherapy port.

    • Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the BP reading prior to enrollment is no greater than 140/90 mmHg.
    • Left ventricular ejection fraction (LVEF) greater than or equal to institutional lower limit of normal.
    • Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, strong CYP3A4 inhibitors are not permitted within 7 days before and during the study, and strong CYP3A4 inducers are not permitted within 12 days before and during the study. A list of drugs that may interact with the cytochrome P450 system is included in Appendix C. Every effort should be made to switch patients taking such agents or substances to other medications 1 week prior to starting therapy, particularly patients with brain metastases who are taking enzyme-inducing anticonvulsant agents (Appendix D). Patients who require potent CYP3A4 inducers or inhibitors and cannot switch medications must have their case reviewed by the Coordinating Center PI and may be enrolled only after discussion with and agreement from the Coordinating Center PI. Current clinical studies with cediranib have not found clinically significant effects on cediranib PK with co-administration of CYP3A4 inducers or inhibitors. Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics (PK) of cediranib will be determined following review of their case by the Coordinating Center PI.
    • Both study agents have been shown to terminate fetal development in the rat, as expected for a process dependent on VEGF signaling. For this reason, women of childbearing potential must have a negative pregnancy test prior to study entry. Women of child-bearing potential and men must agree to use two reliable forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 2 months following study drug discontinuation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    • Patients who are nursing infants: because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with study agents, breastfeeding should be discontinued if the mother is treated with the study agents.
    • Ability to understand and the willingness to sign a written informed consent document.
    • Patients must be able to swallow whole tablets and capsules.

EXCLUSION CRITERIA:

  • Patients must not have received prior treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with bevacizumab is allowed.
  • Patients may not be receiving any other investigational agents.
  • Major surgery within 4 weeks prior to entry into the study, or a surgical incision that is not fully healed.
  • History of familial long QT syndrome, or use of medications that may cause QTc interval prolongation.
  • Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid function in the normal range with medication are ineligible.
  • Warfarin and its derivatives are not allowed. Patient can be receiving low molecular weight heparin if clinically indicated.
  • Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow, retain, and/or absorb the drug are excluded.
  • Patients with any of the following conditions are excluded: serious or non-healing wound, ulcer; history of abdominal fistula, gastrointestinal perforation, or intra -abdominal abscess within 28 days of treatment; coronary/peripheral artery bypass graft or stenting within the past 12 months; or cerebrovascular accident (CVA) or transient ischemic attack within the past 12 months.
  • Greater than 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart or 24-hour urine protein of > 1 g. Patients with < 2+ proteinuria are eligible following initial determination by urinalysis within 1 week prior to enrollment and do not need the urinalysis repeated.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with cediranib or sunitinib. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01391962

Contacts
Contact: Jennifer H Zlott (301) 435-5664 zlottjh@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, California
Santa Monica Oncology Center Recruiting
Santa Monica, California, United States, 90403
Contact: Shivaani Kummar, M.D.    301-435-5402    kummars@mail.nih.gov   
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030-4096
Canada, Ontario
Juravinski Cancer Centre Recruiting
Hamilton, Ontario, Canada, L8V 5C2
Princess Margaret Cancer Center Recruiting
Toronto, Ontario, Canada, M5G2M9
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01391962     History of Changes
Other Study ID Numbers: 110200, 11-C-0200
Study First Received: July 9, 2011
Last Updated: October 15, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Pharmacodynamics
VEGF Inhibitor
Alveolar Soft Part Sarcoma
Anti-Angiogenesis
Gene Expression Profiling

Additional relevant MeSH terms:
Sarcoma
Sarcoma, Alveolar Soft Part
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Neoplasms, Muscle Tissue
Cediranib
Sunitinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014