Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Participants With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia

NCT ID: NCT01088048

Last Updated: 2021-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 241 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-25
• Study Completion Date: 2015-04-28

Brief Summary

The primary objective of the study is to evaluate the safety of idelalisib in combination with an anti-CD20 monoclonal antibody (mAb), a chemotherapeutic agent, a mammalian target of rapamycin (mTOR) inhibitor, a protease inhibitor, an antiangiogenic agent, and/or an immunomodulatory agent in participants with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL).

Conditions

Indolent Non-Hodgkin's Lymphoma; Chronic Lymphocytic Leukemia; Mantle Cell Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Idelalisib + Rituximab

Participants with chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) will receive treatments as follows:

Cohort 1a: Idelalisib (IDELA) 100 mg orally twice daily (BID) on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 intravenously (IV) on Days 1, 8, 15 & 22, Cycles 1 & 2

Cohort 2a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2

Cohort 3e: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2

Cohort 4a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle, starting Cycle 2 Day 1 with the 5th dose of rituximab + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Rituximab

Intervention Type: DRUG

Rituximab administered intravenously

Idelalisib + Rituximab + Bendamustine

Participants with CLL, iNHL and mantle cell lymphoma (MCL) will receive treatments as follows:

Cohort 3a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Cohort 3b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 70 mg/m^2 IV on Days 1 & 2 of each 28-day cycle from Cycles 1 - 6

Cohort 5c: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Rituximab

Intervention Type: DRUG

Rituximab administered intravenously

Bendamustine

Intervention Type: DRUG

Bendamustine administered intravenously

Idelalisib + Bendamustine

Participants with CLL and iNHL will receive treatments as follows:

Cohort 1b: IDELA 100 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Cohort 2b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Cohort 3f: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Cohort 3g: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 70 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Cohort 4b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle starting Cycle 2, Day 3 (after the Cycle 2 bendamustine dosing) + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Bendamustine

Intervention Type: DRUG

Bendamustine administered intravenously

Idelalisib + Ofatumumab

Participants with CLL will receive treatments as follows:

Cohort 3c: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + ofatumumab 12 doses (300 mg (Day 1 or Day 2, Dose 1), followed 1 week later by 1,000 mg weekly for 7 doses (Doses 2 - 8), followed 5 weeks later by 1,000 mg every 4 weeks for 4 doses (Doses 9 - 12))

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Ofatumumab

Intervention Type: DRUG

Ofatumumab administered intravenously

Idelalisib + Fludarabine

Participants with CLL will receive treatments as follows:

Cohort 3d: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + fludarabine 40 mg/m^2 orally on Days 1 - 5 of each 28-day cycle, Cycles 1 - 6

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Fludarabine

Intervention Type: DRUG

Fludarabine administered orally

Idelalisib + Everolimus

Participants with MCL will receive treatments as follows:

Cohort 5a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + everolimus 10 mg orally once daily on Days 1 - 28 of each 28-day cycle

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Everolimus

Intervention Type: DRUG

Everolimus administered orally twice daily until disease progression

Idelalisib + Bortezomib

Participants with MCL will receive treatments as follows:

Cohort 5b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 8 & 15 of each 28-day cycle

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Bortezomib

Intervention Type: DRUG

Bortezomib administered as a subcutaneous injection

Idelalisib + Chlorambucil

Participants with CLL will receive treatments as follows:

Cohort 6a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + chlorambucil 10 mg/m^2 orally once daily for 7 days every 28 days, Cycles 1 - 12

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Chlorambucil

Intervention Type: DRUG

Chlorambucil administered on Days 1-7 every 28 days to allow appropriate therapy for participants with CLL and to coordinate into a cycle period equivalent to other study treatment regimens.

Idelalisib + Rituximab + Chlorambucil

Participants with CLL will receive treatments as follows:

Cohort 6b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + chlorambucil 10 mg/m^2 orally once daily for 7 days every 28 days, Cycles 1 - 12

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Rituximab

Intervention Type: DRUG

Rituximab administered intravenously

Chlorambucil

Intervention Type: DRUG

Chlorambucil administered on Days 1-7 every 28 days to allow appropriate therapy for participants with CLL and to coordinate into a cycle period equivalent to other study treatment regimens.

Idelalisib + Rituximab + Lenalidomide

Participants with CLL and iNHL will receive treatments as follows:

Cohort 7a: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 5 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles

Cohort 7b: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 10 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles

Cohort 7c: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 20 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles

Group Type: EXPERIMENTAL

Idelalisib

Intervention Type: DRUG

Idelalisib tablet administered orally

Rituximab

Intervention Type: DRUG

Rituximab administered intravenously

Lenalidomide

Intervention Type: DRUG

Lenalidomide administered orally

Interventions

Idelalisib

Idelalisib tablet administered orally

Intervention Type: DRUG

Rituximab

Rituximab administered intravenously

Intervention Type: DRUG

Bendamustine

Bendamustine administered intravenously

Intervention Type: DRUG

Ofatumumab

Ofatumumab administered intravenously

Intervention Type: DRUG

Fludarabine

Fludarabine administered orally

Intervention Type: DRUG

Everolimus

Everolimus administered orally twice daily until disease progression

Intervention Type: DRUG

Bortezomib

Bortezomib administered as a subcutaneous injection

Intervention Type: DRUG

Chlorambucil

Chlorambucil administered on Days 1-7 every 28 days to allow appropriate therapy for participants with CLL and to coordinate into a cycle period equivalent to other study treatment regimens.

Intervention Type: DRUG

Lenalidomide

Lenalidomide administered orally

Intervention Type: DRUG

Other Intervention Names

GS-1101; CAL-101; Zydelig®; Rituxan; Treanda; Arzerra; Fludara; Afinitor; RAD-001; Velcade; codenamed PS-341; Leukeran; Revlimid

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18
• Previously treated with relapsed or refractory disease (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen)
• Disease status requirement:

• For CLL patients, symptomatic disease that mandates treatment as defined by the International Workshop on Chronic Lymphocytic Lymphoma (IWCLL) 2008 criteria
• For indolent NHL and MCL patients, measurable disease by CT scan defined as at least 1 lesion that measures > 2 cm in a single dimension
• WHO performance status of ≤ 2
• For men and women of child-bearing potential, willing to use adequate contraception (ie, latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study.

• For Cohort 7 only: Women of child bearing potential must have 2 negative pregnancy tests prior to starting lenalidomide.
• Able to provide written informed consent

Exclusion Criteria

• Is not a good candidate to receive any of the drugs administered in the study for a given disease (idelalisib, bendamustine, rituximab, ofatumumab, fludarabine, everolimus, bortezomib, or chlorambucil), according to the clinical judgment of the investigator
• Patients with atypical immunophenotype with t(11:14) translocation or cyclin D1 over-expression (CLL patients only)
• Had radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 4-weeks prior to the baseline disease status tests
• Had treatment with a short course of corticosteroids for symptom relief within 1-week prior to the baseline disease status tests
• Has had an allogeneic hematopoietic stem cell transplant
• Has known active central nervous system involvement of the malignancy
• Is pregnant or nursing
• Has active, serious infection requiring systemic therapy. Patients may receive prophylactic antibiotics and antiviral therapy at the discretion of the investigator
• Has absolute neutrophil count (ANC) < 1000/µL, unless it is related to underlying CLL, MCL or indolent NHL, the latter documented by > 50% infiltration of bone marrow by tumor cells
• Has platelet count < 75000/µL, unless it is related to underlying CLL, MCL, or iNHL, the latter documented by > 50% infiltration of bone marrow by tumor cells
• Has serum creatinine ≥ 2.0 mg/dL

• For Cohort 7 only: Has creatinine clearance < 60 mL/min
• Has serum bilirubin ≥ 2 mg/dL (unless due to Gilbert's syndrome) for patients with iNHL or CLL; for patients with MCL, serum bilirubin ≥ 1.5 x upper limit of normal
• Has serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥ 2 x upper limit of normal
• Has Child-Pugh Class B or C hepatic impairment
• Has a positive test for HIV antibodies
• Has active hepatitis B or C (confirmed by RNA test). Patients with serologic evidence of prior exposure are eligible.
• Prior treatment with idelalisib

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gilead Study Director

Role: STUDY_DIRECTOR

Gilead Sciences

Locations

Clearview Cancer Institute

Huntsville, Alabama, United States

UCLA

Los Angeles, California, United States

Stanford Cancer Center

Palo Alto, California, United States

Center for Cancer and Blood Disorders

Bethesda, Maryland, United States

Washington University School of Medicine

St Louis, Missouri, United States

Long Island Jewish Medical Center

New Hyde Park, New York, United States

Weill Medical College of Cornell

New York, New York, United States

Willamette Valley Cancer Institute and Research Center

Springfield, Oregon, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

MD Anderson Cancer

Houston, Texas, United States

North Star Lodge Cancer Center

Yakima, Washington, United States

Countries

United States

References

Barrientos JC, Coutre SE, de Vos S, et al. Long-term follow-up of a Phase 1b trial of idelalisib in combination with chemoimmunotherapy in patients with relapsed/refractory chronic lymphocytic leukemia including patients with del17p/TP53 mutation. 51st Annual Meeting of the American Society of Clinical Oncology (ASCO). 29 May-02 June 2015; Chicago, IL, USA. [Poster 7011].

Reference Type: RESULT

Barrientos J, Coutre S, de Vos S, et al. Long-term follow-up of a Phase 1 study evaluating the selective PI3K-delta inhibitor idelalisib in combination with bendamustine (B), bendamustine/rituximab (BR), fludarabine (F), chlorambucil (Chl), Or chlorambucil/rituximab (ChlR) in patients with relapsed or refractory chronic lymphocytic leukemia. Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA, USA. Poster 3343.

Reference Type: RESULT

de Vos S, Wagner-Johnston N, Coutre S, et al. Durable responses following treatment with the PI3K-delta inhibitor idelalisib in combination with rituximab, bendamustine, or both, in recurrent indolent non-Hodgkin lymphoma: Phase I/II results. Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA, USA. Poster 3063.

Reference Type: RESULT

Barrientos J, Leonard J, Furman R, Flinn I, De Vos S, Coutre S, et al. Phase 1b study of idelalisib (GS-1101) plus chlorambucil ± rituximab in patients with relapsed and refractory chronic lymphocytic leukemia (CLL). European Hematology Association (EHA) 2013 Congress, 13-16 June 2013; Stockholm, Sweden. Abstract P100.

Reference Type: RESULT

Barrientos J, Sharman J, De Vos S, et al. GS-1101 (CAL-101), selective phosphatidylinositol 3-Kinase inhibitor, in combination with ofatumumab for treatment of relapsed/refractory chronic lymphocytic leukemia. European Hematology Association (EHA) 2012 Congress, 14-17 June 2012; Amsterdam, The Netherlands. Abstract 1062.

Reference Type: RESULT

Coutre S, Leonard J, Furman R, et al. Combinations of the selective phosphatidylinositol 3 Kinase-delta (PI3Kd) inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): results from a phase 1 study. American Society of Hematology (ASH) Annual Meeting. 8-11 December 2012; Atlanta, GA, USA. Abstract 642.

Reference Type: RESULT

de Vos S, Schreeder M, Finn I, et al. A phase 1 study of the selective phosphatidylinositol 3 Kinase-delta (PI3Kd) inhibitor CAL-101 (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). American Society of Hematology (ASH) 2011 Annual Meeting, 10-13 December 2011; San Diego, CA, USA. Abstract 2699.

Reference Type: RESULT

Flinn I, Schreeder M, Wagner-Johnson N, et al. A phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-Kinase P110δ, in combination with rituximab and/or bendamustine in patients with relapsed or refractory B-cell malignancies. American Society of Hematology (ASH) 2010 Annual Meeting, 04-07 December 2010; Orlando, FL, USA. Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 2832.

Reference Type: RESULT

Flinn I, Schreeder M, Coutre S, et al. A phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-Kinase P110δ, in combination with anti-CD20 monoclonal antibody therapy and/or bendamustine in patients with previously treated B-cell malignancies. 47th Annual Meeting of the American Society of Clinical Oncology (ASCO). 04-08 June 2011; Chicago, IL, USA. [Poster 3064].

Reference Type: RESULT

Fowler N, de Vos S, Schreeder M, et al. Combinations of the phosphatidylinositol 3 Kinase delta (PI3Kd) inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a phase 1 study. American Society of Hematology (ASH) 2012.

Reference Type: RESULT

Furman R, Barrientos J, Sharman J, et al. A phase 1/2 study of the selective phosphatidylinositol 3-Kinase-delta (PI3Kd) inhibitor CAL-101 (GS-1101) with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL). [Poster 6518] 2012 American Society of Clinical Oncology (ASCO) Annual Meeting; 01 05 June, 2012; Chicago, IL, USA. Gilead Sciences, Inc. [Poster 6518].

Reference Type: RESULT

Sharman J, de Vos S, Leonard J, et al. A phase 1 study of the selective phosphatidylinositol 3-Kinase-delta (PI3Kd) inhibitor CAL-101 (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia. American Society of Hematology (ASH) 2011 Annual Meeting, 10-13 December 2011; San Diego, CA, USA. Abstract 1787.

Reference Type: RESULT

Wagner-Johnston ND, De Vos S, Leonard J, Sharman JP, Schreeder MT, Boccia RV, et al. Preliminary results of PI3Kδ inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (MCL) [Abstract 8501]. J Clin Oncol (ASCO Annual Meeting Abstracts) 2013;31 (suppl).

Reference Type: RESULT

Coutre SE, Flinn IW, de Vos S, Barrientos JC, Schreeder MT, Wagner-Johnson ND, Sharman JP, Boyd TE, Fowler N, Dreiling L, Kim Y, Mitra S, Rai K, Leonard JP, Furman RR. Idelalisib in Combination With Rituximab or Bendamustine or Both in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia. Hemasphere. 2018 Apr 25;2(3):e39. doi: 10.1097/HS9.0000000000000039. eCollection 2018 Jun.

Reference Type: DERIVED

PMID: 31723767 (View on PubMed)

de Vos S, Wagner-Johnston ND, Coutre SE, Flinn IW, Schreeder MT, Fowler NH, Sharman JP, Boccia RV, Barrientos JC, Rai KR, Boyd TE, Furman RR, Kim Y, Godfrey WR, Leonard JP. Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma. Blood Adv. 2016 Nov 30;1(2):122-131. doi: 10.1182/bloodadvances.2016000976. eCollection 2016 Dec 13.

Reference Type: DERIVED

PMID: 29296805 (View on PubMed)

Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011 Oct 20;118(16):4313-20. doi: 10.1182/blood-2011-06-338855. Epub 2011 Aug 3.

Reference Type: DERIVED

PMID: 21816833 (View on PubMed)

Other Identifiers

101-07

Identifier Type: -

Identifier Source: org_study_id