Clinical trial NCT01391962: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Sarcoma, Alveolar Soft Part
Keywords: Pharmacodynamics
VEGF Inhibitor
Alveolar Soft Part Sarcoma
Anti-Angiogenesis
Gene Expression Profiling
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-07-12
Enrollment: 34
Sex: ALL
Minimum age (years): 16
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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 vascular endothelial growth factor (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 Response evaluation criteria in solid tumors (RECIST)v1 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 vascular endothelial growth factor (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 Response Evaluation Criteria in Solid Tumors (RECIST)v 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 partial response + complete response (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 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 Response Evaluation Criteria in Solid Tumors (RECIST)v 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 alveolar soft part sarcoma (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 computed tomography (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 principal investigator (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.
* Eastern Cooperative Oncology Group (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
  * aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (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
* QT corrected for heart rate (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 echocardiogram (ECHO):
* 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 millimeters of mercury (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 cytochrome P450 3A4 (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 pharmacokinetic (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 adverse events (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.
* Human immunodeficiency virus (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.

Primary outcomes:
measure: Part I: Objective Response Rate (ORR) of Single-agent Cediranib in Participants With Advanced Alveolar Soft Part Sarcoma (ASPS)
timeFrame: Time on treatment (an average of 497 days or 16 months)
measure: Part I: Objective Response Rate (ORR) of Single-agent Sunitinib in Participants With Advanced Alveolar Soft Part Sarcoma (ASPS)
timeFrame: Time on treatment (an average of 497 days or 16 months)
measure: Part II: Objective Response Rate (ORR) of Sunitinib in Participants Who Progress on the Cediranib Arm During Part I
timeFrame: Time on treatment (an average of 497 days or 16 months)
measure: Part II: Objective Response Rate (ORR) of Cediranib in Participants Who Progress on the Sunitinib Arm During Part I
timeFrame: Time on treatment (an average of 497 days or 16 months)
Secondary outcomes:
measure: Maximum Observed Plasma Concentration of Cediranib
timeFrame: Before first dose on Cycle 1 day 15, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 (each cycle is 28 days)
measure: Percentage of Participants With Progression-free Survival (PFS) at 24 Weeks for Participants Receiving Single-agent Cediranib and Single-agent Sunitinib Malate in Participants With Advanced ASPS During Part I
timeFrame: 24 weeks
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
timeFrame: Date treatment consent signed to date off study, an average of 523 days
Other outcomes:
measure: Best Overall Response During Part I for Participants Who Were Not Newly Diagnosed
timeFrame: Time on treatment (an average of 497 days or 16 months)
measure: Percentage of Participants With Progression-free Survival (PFS) at 24 Weeks During Part I for Participants Who Were Not Newly Diagnosed
timeFrame: 24 weeks
measure: Best Overall Response During Part II for Participants Who Were Not Newly Diagnosed
timeFrame: Time on treatment (an average of 497 days or 16 months)
measure: Percentage of Participants With Progression-free Survival (PFS) at 24 Weeks During Part II for Participants Who Were Not Newly Diagnosed
timeFrame: 24 weeks
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Alice P Chen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson ME, Hornicek FJ, Gebhardt MC, Raskin KA, Mankin HJ. Alveolar soft part sarcoma: a rare and enigmatic entity. Clin Orthop Relat Res. 2005 Sep;438:144-8. doi: 10.1097/01.blo.0000180049.50832.4a.
citation: Azizi AA, Haberler C, Czech T, Gupper A, Prayer D, Breitschopf H, Acker T, Slavc I. Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma. Lancet Oncol. 2006 Jun;7(6):521-3. doi: 10.1016/S1470-2045(06)70729-X. No abstract available.
citation: Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, Klamerus KJ. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs. 2006 Mar;17(3):353-8. doi: 10.1097/00001813-200603000-00015.
citation: Nguyen J, Takebe N, Kummar S, Razak A, Chawla SP, George S, Patel SR, Keohan ML, Movva S, O'Sullivan Coyne G, Do K, Juwara L, Augustine B, Steinberg SM, Kuhlmann L, Ivy SP, Doroshow JH, Chen AP. Randomized Phase II Trial of Sunitinib or Cediranib in Alveolar Soft Part Sarcoma. Clin Cancer Res. 2023 Apr 3;29(7):1200-1208. doi: 10.1158/1078-0432.CCR-22-2145.