Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-chemotherapy

Diffuse Large B-cell Lymphoma Clinical Trial

— PILLAR2  

Official title:

A Randomized, Double-blind, Placebo-controlled, Multi-center Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00790036
• Other study ID #: CRAD001N2301
• Secondary ID: 2008-000498-40
• Status: Completed
• Phase: Phase 3
• First received: November 11, 2008
• Last updated: August 31, 2016
• Start date: July 2009
• Est. completion date: June 2016

Study information

• Verified date: August 2016
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Phase III study of RAD001 adjuvant therapy in poor risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients have achieved complete response with first-line rituximab-chemotherapy

Recruitment information / eligibility

• Status: Completed
• Enrollment: 741
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients with previous histologically confirmed Stage III-IV (or Stage II bulky disease, defined as any tumor mass more than 10 cm in longest diameter), at time of original diagnosis, diffuse large B cell lymphoma (pathology report based on original tumor tissue/lymph node is acceptable for meeting inclusion criteria, but tumor tissue (slides/block) must be available to be sent for central pathology to confirm diagnosis).

2. Patients defined as poor risk with IPI of 3, 4, or 5 at time of original diagnosis.

3. Patients age = 18 years old.

4. Patients must have achieved complete remission (CR) based on the revised IWRC (Cheson et al 2007) following first line R-chemotherapy treatment. Radiation therapy (RT) during or after R-chemotherapy is acceptable provided: 1) it ends 4 weeks prior to start of study drug and, 2) in case of consolidation RT targeted at initial bulky tumor mass, administered after R-chemotherapy, patient is already in CR before initiating RT. Complete remission from R-chemotherapy must be confirmed by clinical and radiologic evaluation along with bone marrow confirmation (if bone marrow was involved by lymphoma before the R-chemotherapy treatment). Local pathology report on the bone marrow biopsy is acceptable. If bone marrow was not involved by lymphoma before R-chemotherapy treatment, then bone marrow confirmation after R-chemotherapy is not required.

5. Patients who received a minimum 5 cycles of R-chemotherapy treatment and maximum 8 cycles of R-chemotherapy treatment. Any variation of CHOP (R-CHOP-14, R-CHOP-21) is acceptable. Liposomal doxorubicin, epirubicin, or pirarubicin (also known as therarubicin) is acceptable. R-EPOCH is acceptable.

6. Patients' last treatment with R-chemotherapy must be 6 to 14 weeks prior to start of study drug.

7. Patients with ECOG performance status (PS) 0, 1, or 2.

8. Patients willing to provide a portion of his/her tumor tissue from original diagnosis or lymph node to confirm diagnosis.

9. The following laboratory values obtained = 21 days prior to start of study drug:

• Absolute neutrophil count = 1000/mm3 (or 1.0 GI/L, SI units)

• Platelet count = 100,000/mm3 (or 100 GI/L, SI units)

• Hemoglobin = 9 g/dL (can be achieved by transfusion)

• Total bilirubin = 2 x ULN (if >2 x ULN direct bilirubin is required and should be =1.5 x ULN)

• AST = 3 x ULN

• Serum creatinine = 2 x ULN

10. Women of childbearing potential must have had a negative serum pregnancy test 14 days prior to the start of study drug plus a negative local urine pregnancy test on Day 1, Cycle 1 prior to treatment and must be willing to use adequate methods of contraception during the study and for 8 weeks after study drug administration.

11. Patients who give a written informed consent obtained according to local guidelines.

12. Patients capable of swallowing intact study medication tablets and following directions regarding taking study drug, or have a daily caregiver who will be responsible for administering study drug.

Exclusion Criteria:

1. Patients with evidence of disease according to the revised IWRC (Cheson et al 2007) after completion of the first-line R-chemotherapy treatment, prior to study entry.

2. Patients receiving ongoing radiation therapy or who received radiation therapy to the residual tumor masses < 4 weeks from start of study drug.

3. Patients who have previously received systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus, etc).

4. Patients with evidence of current central nervous system (CNS) involvement with lymphoma. Patients who have only had prophylactic intrathecal chemotherapy against CNS disease are eligible.

5. Patients with transformed follicular lymphoma.

6. Patients who received ibritumomab tiuxetan (Zevalin®), in order to avoid potential delayed kidney toxicities.

7. Patients who had myelosuppressive chemotherapy or biologic therapy < 3 weeks from start of study drug.

8. Patients receiving chronic systemic immunosuppressive agents. Inhaled and topical steroids are acceptable. Patients may be receiving stable (not increased within the last month) chronic doses of corticosteroids with a maximum dose of 20 mg of prednisone or =5 mg of dexamethasone per day, if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency or asthma.

9. Patients with active, bleeding diathesis.

10. Patients with a known history of HIV seropositivity.

11. Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to any of the excipients.

12. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction = 6 months prior to first study drug, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents = 6 months before study drug start

• severely impaired lung function as defined as spirometry and DLCO that is = 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air

• poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN

• any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study

• nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication

• liver disease such as cirrhosis or decompensated liver disease.

13. Patients who have a history of another primary malignancy = 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix.

14. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes.

15. Patients who are using other investigational agents or who had received investigational drugs = 4 weeks prior to study drug start.

16. Patients unwilling to or unable to comply with the protocol.

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• RAD001
RAD001 10 mg (two 5 mg tablets), daily for 12 months
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	Douglas	Queensland
Australia	Novartis Investigative Site	Geelong	Victoria
Australia	Novartis Investigative Site	Greenslopes	Queensland
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Leoben
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Wien
Austria	Novartis Investigative Site	Wien
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Cambridge	Ontario
Canada	Novartis Investigative Site	Greenfield Park	Quebec
Canada	Novartis Investigative Site	Mississauga	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Québec	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Shanghai
Colombia	Novartis Investigative Site	Bogotá	Cundinamarca
Colombia	Novartis Investigative Site	Bucaramanga
Colombia	Novartis Investigative Site	Medellín
Czech Republic	Novartis Investigative Site	Brno - Bohunice
Czech Republic	Novartis Investigative Site	Hradec Kralove	CZE
Czech Republic	Novartis Investigative Site	Olomouc	CZE
Czech Republic	Novartis Investigative Site	Praha 10
Egypt	Novartis Investigative Site	Alexandria
Egypt	Novartis Investigative Site	Cairo
Egypt	Novartis Investigative Site	Cairo
Egypt	Novartis Investigative Site	Cairo
Egypt	Novartis Investigative Site	Mansoura
France	Novartis Investigative Site	Amiens cedex1
France	Novartis Investigative Site	Brest
France	Novartis Investigative Site	La Roche sur Yon cedex 9
France	Novartis Investigative Site	Limoges cedex
France	Novartis Investigative Site	Pessac
France	Novartis Investigative Site	Saint Priest en Jarez Cedex
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Bad Saarow
Germany	Novartis Investigative Site	Bamberg
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Muenchen
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Heraklion Crete	GR
Greece	Novartis Investigative Site	Ioannina	GR
Hong Kong	Novartis Investigative Site	Hong Kong
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Gyor
Hungary	Novartis Investigative Site	Kaposvár
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szeged
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Tel-Aviv
Italy	Novartis Investigative Site	Brindisi	BR
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Pescara	PE
Italy	Novartis Investigative Site	Piacenza	PC
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Potenza	PZ
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Reggio Emilia	RE
Italy	Novartis Investigative Site	Rozzano	MI
Italy	Novartis Investigative Site	San Giovanni Rotondo	FG
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Venezia	VE
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Kanazawa-city	Ishikawa
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Kure	Hiroshima
Japan	Novartis Investigative Site	Kyoto-city	Kyoto
Japan	Novartis Investigative Site	Matsuyama	Ehime
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Sendai-city	Miyagi
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Suita-city	Osaka
Japan	Novartis Investigative Site	Sunto-gun	Shizuoka
Korea, Republic of	Novartis Investigative Site	Goyang	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Saida
Mexico	Novartis Investigative Site	México	Distrito Federal
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
New Zealand	Novartis Investigative Site	Grafton	Auckland
New Zealand	Novartis Investigative Site	Wellington
Norway	Novartis Investigative Site	Oslo
Peru	Novartis Investigative Site	Jesus Maria	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Poland	Novartis Investigative Site	Bydgoszcz
Poland	Novartis Investigative Site	Warsaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	N. Novgorod
Russian Federation	Novartis Investigative Site	Petrozavodsk
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Saudi Arabia	Novartis Investigative Site	Dammam
Saudi Arabia	Novartis Investigative Site	Jeddah
Saudi Arabia	Novartis Investigative Site	Riyadh
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Cadiz	Andalucía
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadahonda	Madrid
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Pozuelo de Alarcon	Madrid
Spain	Novartis Investigative Site	Sabadell	Barcelona
Spain	Novartis Investigative Site	San Sebastian	Pais Vasco
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Switzerland	Novartis Investigative Site	Bellinzona
Switzerland	Novartis Investigative Site	Zürich	CH
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Songkla
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Talas / Kayseri
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	University Cancer Institute	Boyton Beach	Florida
United States	Lahey Clinic Dept of Lahey Clinic (3)	Burlington	Massachusetts
United States	University of Vermont Office of Clinical Trials Res.	Burlington	Vermont
United States	Ironwood Cancer and Research Centers SC	Chandler	Arizona
United States	Medical University of South Carolina -Hollings Cancer Center MUSC/HCC (2)	Charleston	South Carolina
United States	Levine Cancer Institute Oncology	Charlotte	North Carolina
United States	University of Virginia Health Systems SC-2	Charlottesville	Virginia
United States	Rush University Medical Center Div. of Hematology & Oncology	Chicago	Illinois
United States	University of Colorado Health	Colorado Springs	Colorado
United States	Columbus Regional	Columbus	Georgia
United States	Denver Health & Hospital Authority CACZ885M2301	Denver	Colorado
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD	Fort Worth	Texas
United States	Cancer Centers of the Carolinas Cancer Centers of Carolinas (3	Greenville	South Carolina
United States	Rocky Mountain Cancer Centers RMCC	Greenwood Village	Colorado
United States	Baylor College of Medicine Dept.of Baylor College of Med.	Houston	Texas
United States	University of Texas/MD Anderson Cancer Center Dept of MD Anderson (18)	Houston	Texas
United States	Indiana University Hospital IU Cancer Center	Indianapolis	Indiana
United States	University of California San Diego - Moores Cancer Center Dept of Moores Cancer Ctr (3)	La Jolla	California
United States	Dartmouth Hitchcock Medical Center Dartmouth	Lebanon	New Hampshire
United States	USC/Kenneth Norris Comprehensive Cancer Center Dept.ofNorrisMedicalCenter(4)	Los Angeles	California
United States	Dean Health System	Madison	Wisconsin
United States	The West Clinic	Memphis	Tennessee
United States	University of Tennessee Cancer Institute SC-2	Memphis	Tennessee
United States	Tulane University Health Sciences Center Office of Clinical Research	New Orleans	Louisiana
United States	University of Pittsburgh Medical Center SC-3	Pittsburgh	Pennsylvania
United States	Blue Ridge Research Center at Roanoke Neurological Center SC	Roanoke	Virginia
United States	Mayo Clinic - Rochester Dept. of MayoClinic-Rochester	Rochester	Minnesota
United States	South Texas Oncology and Hematology, PA South Texas Oncology (2)	San Antonio	Texas
United States	Washington University School of Medicine Div. of Medical Oncology	St. Louis	Missouri
United States	Texas A&M HealthSciencesCtr-Scott & White Memorial Hospital CenterForCancerPrevention&Care	Temple	Texas
United States	Waukesha Memorial Hospital Cancer Center Dept.ofWaukeshaMemorialHosp.	Waukesha	Wisconsin
United States	Wake Forest University Baptist Medical Center Dept. of WFUHS	Winston-Salem	North Carolina
Venezuela	Novartis Investigative Site	Caracas	Distrito Capital
Venezuela	Novartis Investigative Site	Caracas	Distrito Capital

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Venezuela,  Argentina,  Australia,  Austria,  Brazil,  Canada,  China,  Colombia,  Czech Republic,  Egypt,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Lebanon,  Mexico,  New Zealand,  Norway,  Peru,  Poland,  Russian Federation,  Saudi Arabia,  Singapore,  Slovakia,  Spain,  Switzerland,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free Survival (DFS) in poor risk patients with DLBCL after achieving CR following first-line R-chemotherapy who receive RAD001 versus patients who receive matching placebo	DFS is the time from date of randomization to the date of event defined as the first documented recurrence of the disease or death due to any cause.	up to 5 years after the last patient is randomized	No
Secondary	Overall survival (OS) in patients who receive RAD001 versus patients who receive matching placebo	OSS is defined as the time from date of randomization to date of death due to any cause. If the patient is not known to have died, survival will be censored at the date of the last contact.	Until 338 438 deaths are observed and after a minimum follow-up of 5 years after the last patient is randomized	Yes
Secondary	Lymphoma-specific surviva (LSS) in patients who receive RAD001 versus patients who receive matching placebo	LSS is defined as time from randomization to death as a result of lymphoma, which means that death must be recorded as a result of lymphoma.	Until 338 438 deaths are observed and after a minimum follow-up of 5 years after the last patient is randomized	Yes
Secondary	Safety profile of RAD001 in comparison to the matching placebo	Number of adverse events in patients who receive RAD001 in comparison to matching placebo.	12 months	Yes