Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4)

• ClinicalTrials.gov Identifier: NCT01491672
• Recruitment Status: Completed
• First Posted: December 14, 2011
• Results First Posted: June 2, 2016
• Last Update Posted: June 6, 2016
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study will evaluate everolimus as second-line therapy in patients with metastatic renal cell carcinoma. Each patient will be enrolled and stratified in one of three cohorts based upon their first-line therapy: 1) prior cytokines, 2) prior sunitinib, or 3) prior anti-VEGF therapy other than sunitinib.

Condition or disease	Intervention/treatment	Phase
Metastatic Renal Cell Carcinoma	Drug: RAD001	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 134 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter Phase II Study to Examine the Efficacy and Safety of Everolimus as Second-line Therapy in the Treatment of Patients With Metastatic Renal Cell Carcinoma
• Study Start Date: November 2011
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: RAD001; Participants, received RAD001 10 mg orally once daily.	Drug: RAD001; Study drug was supplied as 5 mg tablets in blister packs.; Other Name: Everolimus

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) - All Participants [ Time Frame: 20 months ]
   PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. The primary analysis of PFS was based on a local radiology review of CT scans and MRI collected until the participant experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.

Secondary Outcome Measures :

1. Duration of PFS for Each First-line Treatment Cohort [ Time Frame: 20 months ]
   Duration of PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. Participants' assessment was based on the local radiological data according to the RECIST 1.0 Criteria.
2. Overall Survival (OS) [ Time Frame: 28 months ]
   OS was defined as the time from date of enrollment to date of death due to any cause.
3. Clinical Benefit Rate (CBR) [ Time Frame: 20 months ]
   CBR was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease based on the local radiological data according to the RECIST 1.0 criteria.
4. Objective Response Rate (ORR) [ Time Frame: 20 months ]
   ORR was defined as the proportion of participants with best overall response of CR or PR based on the local radiological data according to the RECIST 1.0 Criteria
5. Duration of Response (DoR) [ Time Frame: 20 months ]
   DoR was defined as the time from the first occurrence of PR or CR (as per local radiological review) until the date of the first documented disease progression or death due to underlying cancer.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years old.
2. Patients with advanced renal cell carcinoma of a histological or cytological confirmation of clear cell (or with a component of clear cell) renal carcinoma that have previously progressed on or were intolerant to first-line therapy with sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, or cytokine therapy.
3. Patients must have had prior nephrectomy (partial or total).
4. Patients with at least one measurable lesion at baseline as per the RECIST 1.0 criteria. If skin lesions are reported as target lesions, they should be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion(s) to be determined from the photograph.
5. Patients with a Karnofsky Performance Status ≥ 70%.

6. Adequate bone marrow function as shown by:

   1. ANC ≥ 1.5 x 109/L,
   2. Platelets ≥ 100 x 109/L,
   3. Hemoglobin >9 g/dL

7. Adequate liver function as shown by:

   1. Serum bilirubin ≤ 1.5 x ULN,
   2. ALT and AST ≤ 2.5 x ULN. Patients with known liver metastases may enroll if their AST and ALT ≤ 5 x ULN,
   3. INR < 1.3 (INR < 3 in patients treated with anticoagulants)
8. Adequate renal function: serum creatinine ≤ 2.0 x ULN.
9. Fasting serum cholesterol ≤300 mg/dl OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN.
10. Written informed consent obtained before any trial related activity and according to local guidelines.

Exclusion Criteria:

1. Patients with brain metastases.

2. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal or intrapelvic), open biopsy, or significant traumatic injury to avoid wound healing complications.

   Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry.

3. Patients in anticipation of the need for major surgical procedure during the course of the study.
4. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed up to 2 weeks prior to study treatment start).
5. Patients with a serious non-healing wound, ulcer, or bone fracture.
6. Patients with a history of seizure(s) not controlled with standard medical therapy.
7. Patients who have received more than one prior treatment regimen for metastatic renalcell carcinoma
8. Patients who have received adjuvant therapy for RCC
9. Patients who have previously received systemic mTOR inhibitors (eg, sirolimus, temsirolimus, everolimus)
10. Patients with a known hypersensitivity to everolimus or other rapamycins (eg, sirolimus, temsirolimus) or to its excipients.
11. History or clinical evidence of central nervous system (CNS) metastases.

12. Clinically significant gastrointestinal abnormalities including, but not limited to:

    1. Malabsorption syndrome:
    2. Major resection of the stomach or small bowel that could affect the absorption of study drug
    3. Active peptic ulcer disease
    4. Inflammatory bowel disease:

    i. Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation ii. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.

13. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required.
14. Active bleeding diathesis
15. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 2.0 x ULN.

16. Patients who have any severe and/or uncontrolled medical conditions such as:

    1. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction

       ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia,

    2. active or uncontrolled severe infection,
    3. history of invasive fungal infections,
    4. severe hepatic impairment (Child-Pugh class C),
    5. severely impaired lung function
17. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA) ≤ 6 months before start of study treatment.
18. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
19. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix or breast, and localized cancer of the bladder (T1) and prostate (T1 - T2).
20. Female patients who are pregnant or nursing (lactating).

21. Adults of reproductive potential who are not using effective birth control methods.

    Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in female patients. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug.

22. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start. This should not include sunitinib, sorafenib, axitinib, pazopanib and cytokines.
23. Patients unwilling or unable to comply with the protocol.

Contacts and Locations

Locations

United States, New York

Memorial Sloan Kettering Cancer Center

NY, New York, United States, 90033

Argentina

Novartis Investigative Site

Rio Negro, Viedma, Argentina, 8500

Novartis Investigative Site

Tucuman, Argentina, T4000

Brazil

Novartis Investigative Site

Florianopolis, SC, Brazil, 88034-000

Novartis Investigative Site

Barretos, SP, Brazil, 14784-400

Novartis Investigative Site

São Paulo, SP, Brazil, 01246-000

Novartis Investigative Site

São Paulo, SP, Brazil, 01509-900

Bulgaria

Novartis Investigative Site

Sofia, Bulgaria, 1784

China, Beijing

Novartis Investigative Site

Beijing, Beijing, China, 100730

China, Zhejiang

Novartis Investigative Site

Hangzhou, Zhejiang, China, 310003

China

Novartis Investigative Site

Beijing, China, 100021

Novartis Investigative Site

Guangzhou, China, 510060

Novartis Investigative Site

Shanghai, China, 200032

Russian Federation

Novartis Investigative Site

Leningrad Region, Russia, Russian Federation, 188663

Novartis Investigative Site

Moscow, Russia, Russian Federation, 125284

Novartis Investigative Site

Nizhny Novgorod, Russia, Russian Federation, 603001

Novartis Investigative Site

Obninsk, Russia, Russian Federation, 249036

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yang L, Alyasova A, Ye D, Ridolfi A, Dezzani L, Motzer RJ. RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis. BMC Cancer. 2018 Feb 17;18(1):195. doi: 10.1186/s12885-018-4091-5.

Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. doi: 10.1093/annonc/mdv612. Epub 2015 Dec 17.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01491672
• Other Study ID Numbers: CRAD001L2404; 2010-020447-13 ( EudraCT Number )
• First Posted: December 14, 2011
• Results First Posted: June 2, 2016
• Last Update Posted: June 6, 2016
• Last Verified: June 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Metastatic Renal Cell Carcinoma; Second Line; Everolimus; RAD001

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Everolimus; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs