Phase II Study of Afinitor vs. Sutent in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN)

• ClinicalTrials.gov Identifier: NCT01108445
• Recruitment Status: Completed
• First Posted: April 22, 2010
• Results First Posted: June 20, 2016
• Last Update Posted: January 16, 2018
• Sponsor: Duke University
• Collaborators: Novartis; Pfizer
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: April 20, 2010
• First Posted Date: April 22, 2010
• Results First Submitted Date: February 16, 2016
• Results First Posted Date: June 20, 2016
• Last Update Posted Date: January 16, 2018
• Study Start Date: September 2010
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2016)

Anti-tumor Activity as Measured by Median Progression Free Survival Time [ Time Frame: 24 Months ]

The primary objective will be to compare the anti-tumor activity of everolimus and sunitinib in subjects with mRCC with non-clear cell pathology, as measured by progression-free survival (PFS) following treatment initiation according to RECIST 1.1 criteria. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Original Primary Outcome Measures (submitted: April 20, 2010)

Anti-tumor activity [ Time Frame: 6, 12 and 24 months ]

The primary objective will be to compare the anti-tumor activity of everolimus and sunitinib in subjects with mRCC with non-clear cell pathology, as measured by progression-free survival (PFS) following treatment initiation according to RECIST criteria. In addition, the rates of PFS will be compared at 6, 12 and 24 months.

Current Secondary Outcome Measures (submitted: December 15, 2017)

• Progression Free Survival Rates [ Time Frame: 6, 12 and 24 months ]
  6-, 12-, and 24-month rates of PFS in each arm will be compared for each treatment arm. Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• PFS Expressed in Months [ Time Frame: 24 months ]
  Progression-free survival (PFS) expressed in months as compared to an historic control (interferon-treated clear cell RCC control arm from the sunitinib phase III study). Progressive disease is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• Overall Response Rate [ Time Frame: 24 months ]
  Defined as complete response [CR] and partial response [PR] by RECIST 1.1 criteria in each treatment arm.Overall Response Rate (ORR) = CR + PR. Complete Response (CR) is 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) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
• Percentage of Participants With Stable Disease (SD) [ Time Frame: Baseline to 36 months ]
  Percentage of participants with stable disease during treatment is defined as stable disease [SD] by RECIST 1.1 criteria as calculated in each treatment arm. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• 12 Week Clinical Benefit Rate as Percentage [ Time Frame: Baseline to 36 months ]
  Rate of complete or partial response or stable disease by the RECIST 1.1 criteria lasting ≥ 12 weeks prior to progression. Benefit rate is defined as complete response [CR] and partial response [PR] and stable disease [SD] by RECIST 1.1 criteria in each treatment arm. Benefit rate = CR + PR + SD. Complete Response (CR) is 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) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• Overall Survival Rates [ Time Frame: 6, 12, 24, 36 months ]
  To compare overall survival (OS) rates at 6, 12, 24, and 36 months and over time in each treatment arm.
• Best Tumor Shrinkage as a Percentile in Each Arm [ Time Frame: 24 months ]
  To compare the best tumor shrinkage as a percentile in each treatment arm. The percentile change at each follow up visit is calculated by measuring the percentage change in the Sum of lesion measurement from baseline. The best tumor shrinkage is lowest percentile change. A decrease is indicated by a negative percentage.
• Median Duration of Response (CR, PR, and SD) [ Time Frame: 24 months ]
  To compare the median duration of response (CR, PR, and SD) in each treatment arm. According to RECIST 1.1, Complete Response (CR) is 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) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• Median OS [ Time Frame: Up to 40 months ]
  To compare the median OS in each treatment arm.
• Time-to-new Metastatic Disease in Each Treatment Arm [ Time Frame: 36 months ]
  To compare the time-to-new metastatic disease in each treatment arm, defined from the date of first study agent administration to the onset of a new evaluable site of disease, excluding the primary site and all sites documented at baseline
• Percentage of Participants With Adverse Events [ Time Frame: 24 months ]
  To assess toxicities associated with everolimus or sunitinib using NCI CTC version 4.0 criteria
• Change in Quality-of-life [ Time Frame: baseline, cycle 3 day 1 ]
  To compare change in quality-of-life, as measured by the FACT-KSI scale at baseline and cycle 3 day 1 per subject in each treatment arm. Functional Assessment of Cancer Therapy Kidney Symptom Index. FKSI is a questionnaire for FACT-Kidney Symptom Index used to assess QoL/participant-reported outcomes for participants diagnosed with renal cell cancer. The FKSI contained 15 questions each ranging from 0 (not at all) to 4 (very much) so that FKSI ranged between 0-60 where higher scores reflects better functioning and fewer symptoms.
• Change in Quality-of-life [ Time Frame: baseline, cycle 6 day 1 ]
  To compare change in quality-of-life, as measured by the FACT-KSI scale at baseline and cycle 6 day1 per subject in each treatment arm. Functional Assessment of Cancer Therapy Kidney Symptom Index. FKSI is a questionnaire for FACT-Kidney Symptom Index used to assess QoL/participant-reported outcomes for participants diagnosed with renal cell cancer. The FKSI contained 15 questions each ranging from 0 (not at all) to 4 (very much) so that FKSI ranged between 0-60 where higher scores reflects better functioning and fewer symptoms.
• Change in Quality-of-life [ Time Frame: baseline, up to 40 months ]
  To compare change in quality-of-life, as measured by the FACT-KSI scale at baseline and end of treatment per subject in each treatment arm. Functional Assessment of Cancer Therapy Kidney Symptom Index. FKSI is a questionnaire for FACT-Kidney Symptom Index used to assess QoL/participant-reported outcomes for participants diagnosed with renal cell cancer. The FKSI contained 15 questions each ranging from 0 (not at all) to 4 (very much) so that FKSI ranged between 0-60 where higher scores reflects better functioning and fewer symptoms.

Original Secondary Outcome Measures (submitted: April 20, 2010)

Safety, tolerablity, QOL [ Time Frame: 6, 12 and 24 months ]

Comparison of antitumor activity of these agents against historic interferon-treated controls, as well as safety, tolerability, and QOL will be measured. Overall response rates and degree of tumor shrinkage, overall survival, and time to new metastases will be compared. Tumor, plasma and urine biomarkers will be correlated with response and PFS in these patients, with an emphasis on mTOR pathway and VEGF pathway activation, DNA polymorphisms and mutational analysis, and longitudinal plasma/urine angiokine levels.

Current Other Pre-specified Outcome Measures (submitted: December 15, 2017)

• Clinical Measures of Response and PFS With Baseline and Time-dependent Levels of Biomarkers [ Time Frame: 36 months ]
  To correlate clinical measures of response and PFS with baseline and time-dependent levels of biomarkers. These biomarkers include plasma angiokine levels, tissue immunohistochemical and genomic profiles, copy number as assessed by array-based comparative genomic hybridization (CGH), and known mutations in non-clear cell RCC
• Changes in Copy Number, RNA Expression, and Immunohistochemical Profiles [ Time Frame: 36 months ]
  To evaluate in an exploratory fashion changes in copy number, RNA expression, and immunohistochemical profiles by microarray between primary non-clear cell RCC tumors and metastatic samples

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase II Study of Afinitor vs. Sutent in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma
• Official Title: A Randomized Phase II Study of Afinitor (RAD001) vs. Sutent (Sunitinib) in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN)
• Brief Summary: To compare the anti-tumor activity of everolimus and sunitinib in subjects with metastatic renal cell carcinoma (mRCC) with non-clear cell pathology.
• Detailed Description: This will be an international (USA, Canada, and UK) open-label, outpatient, multicenter, randomized study of treatment with RAD001 (everolimus (Afinitor®) or sunitinib (Sutent®) in subjects with mRCC and non-clear cell histology. Special emphasis is placed on papillary and chromophobe histologies while sarcomatoid clear cell variants, medullary, and collecting duct carcinomas will be excluded (see eligibility). Subjects may continue receiving study drugs until disease progression, unacceptable toxicities, or withdrawal of consent, for a maximum of 24 months. Continuation of study assigned treatment will be allowed beyond 24 months at the discretion of the sponsor. Stratification variables will include histology (papillary vs. chromophobe) and Motzer risk criteria (0, 1-2, and 3). Tumor progression will be assessed locally and by independent review, in strict accordance with Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria measured every 12 weeks. At the time of progression, subjects will be taken off study other than simple administrative mortality follow-up. Primary pathologic samples and plasma/urine angiokine levels at baseline and over time will be collected and stored centrally for biomarker analysis.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Non-clear Cell Renal Cell Carcinoma

Intervention

• Drug: Everolimus
  Subjects in this treatment arm will receive everolimusRAD001 10 mg orally once daily by mouth on days 1 through 42 for each 42 day cycle.
  Other Name: Afinitor, everolimus, RAD001
• Drug: Sunitinib
  50 mg daily by mouth on days 1 through 28 of each 42 day cycle.
  Other Name: Sutent

Study Arms

• Active Comparator: RAD001
  Subjects in this treatment arm will receive everolimus/RAD001 10 mg orally once daily by mouth on days 1 through 42 for each 42 day cycle.
  Intervention: Drug: Everolimus
• Active Comparator: Sunitinib
  Subjects in this treatment arm will take sunitinib 50 mg daily by mouth on days 1 through 28 of each 42 day cycle.
  Intervention: Drug: Sunitinib

Publications *

• Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-388. doi: 10.1016/S1470-2045(15)00515-X. Epub 2016 Jan 13.
• Winquist E, Rodrigues G. Open clinical uro-oncology trials in Canada. Can J Urol. 2012 Dec;19(6):6587-91. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 11, 2016): 131
• Original Estimated Enrollment (submitted: April 20, 2010): 108
• Actual Study Completion Date: April 2015
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed advanced Renal Cell Carcinoma (RCC), with non-clear cell pathology.
2. RCC tumor tissue available for correlative sciences, from either primary or metastatic site or both.
3. At the time of screening, at least 4 weeks since prior palliative radiation therapy and/or major surgery, and resolution of all toxic effects of prior therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.0) Grade 1.
4. Subject must have radiographic evidence of metastatic disease with at least 1 measurable per RECIST 1.1 criteria (Attachment 1)].
5. Age > 18 years.
6. Adequate laboratory values
7. Karnofsky Performance Status ≥ 60 (Attachment 2).
8. Life expectancy of at least 3 months.
9. Written, signed, dated, and witnessed Institutional Review Board (IRB) or Institutional Ethics Committee (IEC) approved informed consent form (ICF) before any screening procedures are performed.

Exclusion Criteria:

1. Subjects with a history of or active central nervous system (CNS) metastases.
2. Prior systemic therapy for RCC, including mTOR and anti-angiogenic therapy, chemotherapy, biologic or experimental therapy.
3. Subjects with collecting duct, medullary, small cell, oncocytoma, or lymphoma-type pathology.
4. Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers.
5. Major surgery, open biopsy, traumatic injury, or radiotherapy within 4 weeks of the screening visit.
6. Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy.
7. Presence of a non-healing wound or ulcer.
8. Grade 3 hemorrhage within the past month.
9. Hypertension with systolic blood pressure of >180 mm Hg and/or diastolic pressure >100 mm Hg.
10. Subjects with American Heart Association (AHA) Class 2-4 heart disease or any history of congestive heart failure with an ejection fraction <50%, or history of unstable angina, myocardial infarction, coronary artery bypass graft, cerebrovascular accident, transient ischemic attack, or pulmonary embolism within 6 months of entry.
11. Diabetes mellitus with glycosylated hemoglobin A1c (HbgA1c) > 10% despite therapy.
12. A history of interstitial pneumonitis.
13. Subjects with active autoimmune disorder(s) being treated with immunosuppressive agents within 4 weeks prior to the screening visit.
14. Subjects receiving immunosuppressive agents and those with chronic viral/bacterial/fungal illnesses such as human immunodeficiency virus (HIV).
15. Patients who have receive immunization with attenuated live vaccines within one week of study entry or during study period.
16. Patients with active infection(s), active antimicrobial therapy or serious intercurrent illness.
17. History of other prior malignancy in past 5 years.
18. Pregnant or nursing women.
19. Major medical/psychiatric illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study, including inability to absorb oral medications and history of noncompliance to medical regimens.
20. Known hypersensitivity to any of the components in everolimus or sunitinib product
21. Subjects taking agents that significantly prolong the QTc interval are not eligible.
22. Proteinuria with a spot urine protein/creatinine ratio >2 or 24 hour urine protein >2 grams per 24 hours.
23. Severely impaired lung function as defined as spirometry and Carbon Monoxide Diffusing Capacity (DLCO) that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air.
24. Advanced liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United Kingdom, United States

Administrative Information

• NCT Number: NCT01108445
• Other Study ID Numbers: Pro00020714; CRAD001L2402T ( Other Identifier: Novartis )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Duke University
• Original Responsible Party: Andrew Armstrong, MD, ScM, Duke Univeristy Medical Center
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current

Collaborators

• Novartis
• Pfizer

Investigators

• Principal Investigator: Andrew Armstrong, MD, ScM; Duke University

• PRS Account: Duke University
• Verification Date: September 2017