Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Idelalisib in Adults Receiving Ruxolitinib as Therapy for Primary, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis With Progressive or Relapsed Disease

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics of idelalisib in adults receiving ruxolitinib as therapy for intermediate to high-risk primary myelofibrosis (PMF), post-polycythemia vera, or post-essential thrombocythemia myelofibrosis (post-PV MF or post-ET MF) with progressive or relapsed disease. This is a dose-escalation study. There will be 4 cohorts (A, B, C, D). Participants will receive an escalating dose or dose frequency of idelalisib based on the safety data of available cohort(s).

Official Title
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A Phase 1b Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Idelalisib in Subjects Receiving Ruxolitinib as Therapy for Primary, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis With Progressive or Relapsed Disease

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals must have been on a stable dose of ruxolitinib for at least 4 weeks prior to study entry Individuals with PMF, post-PV MF, or post-ET MF classified as high risk or intermediate risk as defined by the Dynamic International Prognostic Scoring System (DIPSS) for PMF or DIPSS Plus, if cytogenetics are available Individuals with PMF, post-PV MF, or post-ET MF who are receiving ruxolitinib and meet 2013 Revised International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) response criteria with progressive and relapsed disease, with modifications for progressive disease complete remission (CR), partial remission (PR), or clinical improvement (CI) European Cooperative Oncology Group (ECOG) performance status of ≤ 2 Required screening laboratory values as described in the protocol 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 jiroveci pneumonia (PJP) Able to understand and willing to sign the informed consent form Key Exclusion Criteria: Individuals on a stable ruxolitinib dose of 5 mg once daily History of prior allogeneic bone marrow progenitor cell or solid organ transplantation Ongoing drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver Ongoing drug-induced pneumonitis Ongoing inflammatory bowel disease Ongoing alcohol or drug addiction Symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication Known hypersensitivity to the study investigational medicinal product (IMP), the metabolites, or formulation excipients Unwilling or unable to take oral medication Unresolved non-hematologic toxicities from prior therapies that are > Common terminology Criteria for Adverse Events (CTCAE) Grade 1 (with the exception of alopecia [Grade 1 or 2 permitted]) Pregnant or lactating females Cytomegalovirus (CMV): Ongoing infection, treatment, or prophylaxis within the past 28 days 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A, Idelalisib + Ruxolitinib<br>Idelalisib 50 mg once daily in participants receiving ruxolitinib. | Drug: Idelalisib<br>* Idelalisib tablets administered orally for 24 weeks<br>* Other names: GS-1101;Drug: Ruxolitinib<br>* Ruxolitinib will be administered per standard of care according to package insert<br>|
| Experimental: Cohort B, Idelalisib + Ruxolitinib<br>Idelalisib 50 mg twice daily in participants receiving ruxolitinib. | Drug: Idelalisib<br>* Idelalisib tablets administered orally for 24 weeks<br>* Other names: GS-1101;Drug: Ruxolitinib<br>* Ruxolitinib will be administered per standard of care according to package insert<br>|
| Experimental: Cohort C, Idelalisib + Ruxolitinib<br>Idelalisib 150 mg once daily in participants receiving ruxolitinib. | Drug: Idelalisib<br>* Idelalisib tablets administered orally for 24 weeks<br>* Other names: GS-1101;Drug: Ruxolitinib<br>* Ruxolitinib will be administered per standard of care according to package insert<br>|
| Experimental: Cohort D, Idelalisib + Ruxolitinib<br>Idelalisib 150 mg twice daily in participants receiving ruxolitinib. | Drug: Idelalisib<br>* Idelalisib tablets administered orally for 24 weeks<br>* Other names: GS-1101;Drug: Ruxolitinib<br>* Ruxolitinib will be administered per standard of care according to package insert<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Any Treatment Emergent Adverse Events Within 28 Days of Idelalisib Exposure |  | First dose date up to 28 days | 
| Percentage of Participants Experiencing Adverse Events Related to Idelalisib Within 28 Days of Idelalisib Exposure |  | First dose date up to 28 days | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities Within 28 Days of Idelalisib Exposure by Worst Grade at Postbaseline | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 where 1=Mild, 2=Moderate, 3=Severe, 4=Potentially Life Threatening. | First dose date up to 28 days | 
| Percentage of Participants Who Permanently Discontinued Idelalisib Due to an Adverse Event Within 28 Days of Idelalisib Exposure |  | First dose date up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment Emergent Adverse Events Beyond 28 Days of Idelalisib Exposure |  | First dose date up to the last dose date (maximum:15.1 months) plus 30 days | 
| Percentage of Participants Experiencing Adverse Events Related to Idelalisib Beyond 28 Days of Idelalisib Exposure |  | First dose date up to the last dose date (maximum:15.1 months) plus 30 days | 
| Percentage of Participants Experiencing Abnormal Laboratory Abnormalities Beyond 28 Days of Idelalisib Exposure by Worst Grade at Postbaseline | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 where 1=Mild, 2=Moderate, 3=Severe, 4=Potentially Life Threatening. | First dose date up to the last dose date (maximum:15.1 months) plus 30 days | 
| Percentage of Participants Who Permanently Discontinued Idelalisib Due to an Adverse Event Beyond 28 Days of Exposure |  | First dose date up to the last dose date (maximum:15.1 months) plus 30 days | 
| Rate of Overall Response | Rate of overall response as defined by 2013 Revised International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) response criteria. | Start of treatment to end of treatment ( up to 15.1 months) | 
| Plasma Concentration of Idelalisib and GS-563117 (Idelalisib Metabolite) |  | Predose Week 2, 1.5 hour Week 2, and Predose Week 3 |