Clinical Trials /

Sunitinib or Cediranib for Alveolar Soft Part Sarcoma

NCT01391962

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: - 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.

Related Conditions:
  • Alveolar Soft Part Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sunitinib or Cediranib for Alveolar Soft Part Sarcoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 110200
  • SECONDARY ID: 11-C-0200
  • NCT ID: NCT01391962

Conditions

  • Sarcoma, Alveolar Soft Part

Interventions

DrugSynonymsArms
CediranibPart I
SunitinibPart II

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.

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:

        -  Two sets of patients will be enrolled and assessed in separate cohorts: a) patients with
           non-newly diagnosed ASPS and b) patients with newly diagnosed ASPS

        -  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. As of May 6, 2019, we have closed the
           cediranib arm of the newly diagnosed ASPS cohort due to inadequate activity per the
           statistical plan; all newly diagnosed ASPS patients will be assigned to the sunitinib
           malate treatment arm.

        -  Part II: At the time of disease progression, patients will cross over to the other
           treatment arm after a 2-week wash-out period. As of May 6, 2019, patients in the newly
           diagnosed ASPS cohort are not eligible to cross over to the cediranib treatment arm,
           which was closed due to inadequate activity.

        -  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.
    

Trial Arms

NameTypeDescriptionInterventions
Part IExperimentalPatients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, once a day in 28-day cycles
  • Cediranib
  • Sunitinib
Part IIExperimentalAt the time of disease progression patients will cross over to the other treatment arm after a 2-week wash-out period.
  • Cediranib
  • Sunitinib

Eligibility 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.
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the objective response rate (ORR) of single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS.
Time Frame:24 weeks
Safety Issue:
Description:Objective responses will be determined by RECIST criteria

Secondary Outcome Measures

Measure:Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib and single-agent sunitinib malate in patients with advanced ASPS
Time Frame:4 and 6 months
Safety Issue:
Description:
Measure:Perform pharmacokinetic analysis for cediranib
Time Frame:At the time of progression
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Pharmacodynamics
  • VEGF Inhibitor
  • Alveolar Soft Part Sarcoma
  • Anti-Angiogenesis
  • Gene Expression Profiling

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