Clinical trial NCT01088048: 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
Official title: A Phase I Study to Investigate the Safety and Clinical Activity of Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 mAb in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Indolent Non-Hodgkin's Lymphoma
Chronic Lymphocytic Leukemia
Mantle Cell Lymphoma
Keywords: phosphatidylinositol 3-kinase
Ofatumumab
indolent non-Hodgkin lymphoma (iNHL)
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2010-03-17
Enrollment: 241
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Key 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

Key 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

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Duration of Exposure to IDELA
timeFrame: First dose date up to 12 months
measure: Toxicity of Administration of IDELA
timeFrame: First dose date up to 5 years
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Up to 5 years
measure: Duration of Response
timeFrame: Up to 5 years
measure: Time to Response
timeFrame: Up to 5 years
measure: Progression-free Survival
timeFrame: Up to 5 years
measure: Overall Survival
timeFrame: Up to 5 years
measure: Plasma Concentration of IDELA (Cohort 1, Cohorts 2 and 3, Cohort 5)
timeFrame: Predose, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 hours postdose at Week 0; predose, 1.5 hours postdose at Weeks 4, 12, and 24
measure: Plasma Concentration of IDELA (Cohort 4)
timeFrame: Predose at Week 0; predose, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 hours postdose at Week 4; predose, 1.5 hours postdose at Week 12; and predose, 1.5 hours postdose at Week 24
measure: Plasma Concentration of IDELA (Cohort 6)
timeFrame: Predose, 1.5 hours postdose at Weeks 0, 4, 12 and 24
measure: Plasma Concentration of IDELA (Cohort 7)
timeFrame: Predose, 1.5 hours postdose at Weeks 0, 5 and 13
measure: Sub-study: Plasma Concentration of IDELA (Cohorts 1-4)
timeFrame: pre dose and 0.5, 1, 1.5, 2.0, 3.0, 4.0, and 6.0 hours post dose
measure: Plasma Concentration of Bendamustine
timeFrame: Predose, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 hours postdose at Week 0
measure: Plasma Concentration of Everolimus
timeFrame: Predose, 1.5 hours postdose at Weeks 0 and 4
measure: Plasma Concentration of Lenalidomide
timeFrame: Predose, 1.5 hours postdose at Week 1 and predose at Week 5
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Clearview Cancer Institute
state: Alabama
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell
state: New York
city: Springfield
country: United States
facility: Willamette Valley Cancer Institute and Research Center
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer
state: Texas
city: Yakima
country: United States
facility: North Star Lodge Cancer Center
state: Washington
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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].
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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].
citation: 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.
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