Dose Optimization Study of Idelalisib in Follicular Lymphoma

Study Overview
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Brief Summary
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The primary objective of this study is to establish a safe and effective dosing regimen of idelalisib in participants with relapsed or refractory follicular lymphoma (FL) who have no other therapeutic options.

Official Title
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Dose Optimization Study of Idelalisib in Follicular Lymphoma

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Idelalisib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed diagnosis of B-cell follicular lymphoma (FL), and grade limited to 1, 2, or 3a based on criteria established by the World Health Organization (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissues Relapsed or refractory FL and have received at least 2 lines of prior therapy for FL and have no other available therapeutic options. Note: Rituximab maintenance is not routinely considered a separate line of therapy when it is given as part of the prior rituximab-containing regimen given over a number of cycles followed by maintenance. Rituximab monotherapy may be considered a separate line of therapy when disease relapse occurs between the initiation of rituximab monotherapy and the preceding line of therapy. If there are any ambiguities about eligibility, the site should consult with the medical monitor. Ann-Arbor Stage 2 (non-contiguous), 3, or 4 disease per Lugano Classification Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥ 1 lesion that measures ≥ 1.5 cm in the longest dimension (LD) and ≥ 1.0 cm in the longest perpendicular dimension (LPD) as assessed by positron emission tomography-computed tomography (PET-CT), computed tomography (CT) or magnetic resonance imaging (MRI) Required baseline central laboratory data in protocol. For female individuals of childbearing potential and male individuals of reproductive potential, willingness to use a protocol- recommended method of contraception Lactating females must agree to discontinue nursing Willing and able to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions including mandatory prophylaxis for Pneumocystis jirovecii pneumonia (PJP) Key Exclusion Criteria: History of lymphoid malignancy other than FL (eg, diffuse large B-cell lymphoma) Known history of, or clinically apparent, central nervous system (CNS) lymphoma or leptomeningeal lymphoma. Known presence of intermediate- or high-grade myelodysplastic syndrome. Known history of serious allergic reaction including anaphylaxis or Stevens- Johnson syndrome/ toxic epidermal necrolysis History of a non-lymphoid malignancy except for protocol allowed exceptions Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of enrollment Known history of drug-induced liver injury, chronic active hepatitis B virus (HBV), chronic active hepatitis C virus (HCV), alcoholic liver disease, non-alcoholic steatohepatitis, cirrhosis of the liver, portal hypertension, primary biliary cirrhosis, or ongoing extrahepatic obstruction caused by cholelithiasis History of or ongoing drug-induced pneumonitis History of or ongoing inflammatory bowel disease Known human immunodeficiency virus (HIV) infection History of prior allogeneic bone marrow progenitor cell or solid organ transplantation Ongoing immunosuppressive therapy, including systemic corticosteroids (> 10 mg prednisone or equivalent/day) with the exception of the use of topical, enteric, or inhaled corticosteroids as therapy for comorbid conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia Concurrent participation in another therapeutic clinical trial Prior treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors Cytomegalovirus (CMV): Ongoing infection, treatment, or specifically CMV antiviral prophylaxis within 28 days prior to the screening visits CMV test Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: As of protocol amendment 5, the Idelalisib 100 mg arm is closed to enrollment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib 150 mg BID<br>Participants will receive idelalisib 150 mg twice daily continuously. For participants enrolled prior to protocol amendment 5: Based on the independent review committee (IRC) response assessment, participants may be discontinued from the study or may receive blinded or open-label idelalisib 150 mg twice daily. | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: CAL-101;|
| Experimental: Idelalisib 100 mg BID<br>Participants will receive idelalisib 100 mg twice daily continuously. Based on the IRC response assessment, participants may either be dose escalated to open-label 150 mg twice daily or maintain blind and continue on idelalisib 100 mg twice daily. As of protocol amendment 5, enrollment to this arm has been closed. | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: CAL-101;|
| Experimental: Idelalisib 150 mg BID INT<br>Participants will receive idelalisib 150 mg twice daily in 28-day cycles with 21 days on-treatment and 7 days off-treatment. | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: CAL-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as percentage of participants who achieve a partial response (PR) or complete response (CR). PR criteria: No evidence of new disease, a ≥50% decrease from baseline in sum of products of diameters (SPD) of index lesions, no increase in non-index disease, no increase in liver/spleen size and no new liver/spleen enlargement. Persistence of bone marrow involvement in a participant who meets other criteria for CR based on the disappearance of all nodal and extra-nodal masses. CR criteria: No evidence of new disease, regression of all index nodal lesions to normal size (≤1.5 cm in longest dimension (LD) for large nodes and ≤1.0 cm in LD, ≤1.0 cm in longest perpendicular dimension (LPD) for small nodes), regression to normal of all nodal non-index disease, disappearance of all detectable extra-nodal index and non-index disease, normal spleen and liver size, no new liver/spleen enlargement, morphologically negative bone marrow. | Randomization up to end of treatment (maximum duration: 73.5 months) | 
| Number of Participants With Grade 4 or Higher Treatment-Emergent Adverse Events (TEAEs) | TEAEs were defined as 1 or both of any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. | First dose date up to 30 days after last dose of study drug (maximum 64.6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR: interval from first documentation of CR/PR to earlier of first documentation of disease progression (PD) by independent review committee (IRC)/death from any cause. PR:No evidence of new disease,≥50% decrease from baseline in SPD of index lesions,no increase in non-index disease, no increase in liver/spleen size,no new liver/spleen enlargement; Persistence of bone marrow involvement in participant who meets other CR criteria. CR: No evidence of new disease,regression of all index nodal lesions to normal size (large nodes:≤1.5 cm in LD;small nodes:≤1.0 cm in LD,≤1.0 cm in LPD), regression to normal of all nodal non-index disease,disappearance of all detectable extra-nodal index,non-index disease,normal spleen and liver size, no new liver/spleen enlargement; PD: New node of >1.5 cm or >1.0 to ≤1.5 cm in LD, >1.0 cm in LPD, new/unequivocal reappearance of resolved extra-nodal lesion,new non-index disease,increase by 50% in SPD of index lesions,LD of individual node/extra-nodal mass. | From first documentation of CR or PR until PD or death from any cause (maximum duration: 73.5 months) | 
| Overall Response Rate (ORR) by Week 24 | ORR by Week 24 is defined as the percentage of participants who achieve a PR or CR by Week 24. PR criteria: No evidence of new disease, a 50% decrease from baseline in SPD of index lesions, no increase in non-index disease, no increase in liver/spleen size and no new liver/spleen enlargement. CR criteria: No evidence of new disease, regression of all index nodal lesions to normal size (≤1.5 cm in LD for large nodes and ≤1.0 cm in LD, ≤1.0 cm in LPD for small nodes), regression to normal of all nodal non-index disease, disappearance of all detectable extra-nodal index and non-index disease, normal spleen and liver size, no new liver/spleen enlargement, morphologically negative bone marrow. | First dose date up to Week 24 | 
| Number of Participants With Any TEAE, Grade 3 or Higher TEAEs, Serious TEAEs, Idelalisib-related TEAEs, TEAEs Leading to Interruption or Discontinuation of Idelalisib | TEAEs were defined as 1 or both of any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. TEAEs severity was graded according to the NCI CTCAE version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants are counted at the highest AE grade experienced. | First dose date up to 30 days after last dose of study drug (maximum 64.6 months) | 
| Number of Participants With Clinically Significant Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time postbaseline up to and including the date of last study drug dose plus 30 days. Laboratory abnormalities included hematology and serum chemistry parameters. Clinically significant laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for severity as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (life threatening). The number of participants with any post-baseline abnormal laboratory value in Grade 1-4 categories are reported. | First dose date up to 30 days after last dose of study drug (maximum 64.6 months) | 
| Time to Onset of Adverse Events of Interest (AEIs) | Time to onset of AEIs is defined as the interval (in months) from the start of idelalisib treatment to the first documentation of start of AEI. AEIs included grade ≥ 3 diarrhea/colitis, rash, febrile neutropenia, infection, and any grade of: Pneumonitis, bowel perforation, progressive multifocal leukoencephalopathy (PML), Pneumocystis jirovecii pneumonia (PJP), cytomegalovirus (CMV) infection, and organizing pneumonia. | First dose date up to 30 days after last dose of study drug (maximum 64.6 months) | 
| Progression-Free Survival (PFS) | PFS is defined as the interval (in months) from randomization to the earlier of the first documentation of PD by IRC or death from any cause. PD criteria: New node of >1.5 cm or >1.0 cm to ≤1.5 cm in LD, >1.0 cm in LPD, new/unequivocal reappearance of resolved extra-nodal lesion, new non-index disease, increase by 50% in SPD of index lesions, LD of individual node/extra-nodal mass. | Randomization up to PD or death from any cause (maximum duration: 73.5 months) | 
| Overall Survival (OS) | OS is defined as the interval (in months) from randomization to death from any cause. | Randomization up to death from any cause (maximum duration: 73.5 months) | 
| Trough Plasma Concentration of Idelalisib |  | Predose on Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 32, and 48 | 
| Peak Plasma Concentration of Idelalisib |  | 1.5 hours postdose on Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 32, and 48 |