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 (Madison)

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

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).

Study Overview

• Status: Terminated
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: Idelalisib; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A, Idelalisib + Ruxolitinib; Idelalisib 50 mg once daily in participants receiving ruxolitinib.	Drug: Idelalisib; Idelalisib tablets administered orally for 24 weeks; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Ruxolitinib; Ruxolitinib will be administered per standard of care according to package insert
Experimental: Cohort B, Idelalisib + Ruxolitinib; Idelalisib 50 mg twice daily in participants receiving ruxolitinib.	Drug: Idelalisib; Idelalisib tablets administered orally for 24 weeks; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Ruxolitinib; Ruxolitinib will be administered per standard of care according to package insert
Experimental: Cohort C, Idelalisib + Ruxolitinib; Idelalisib 150 mg once daily in participants receiving ruxolitinib.	Drug: Idelalisib; Idelalisib tablets administered orally for 24 weeks; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Ruxolitinib; Ruxolitinib will be administered per standard of care according to package insert
Experimental: Cohort D, Idelalisib + Ruxolitinib; Idelalisib 150 mg twice daily in participants receiving ruxolitinib.	Drug: Idelalisib; Idelalisib tablets administered orally for 24 weeks; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Ruxolitinib; Ruxolitinib will be administered per standard of care according to package insert

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2015
• Primary Completion (Actual): November 20, 2017
• Study Completion (Actual): November 20, 2017

Study Registration Dates

• First Submitted: May 1, 2015
• First Submitted That Met QC Criteria: May 5, 2015
• First Posted (Estimate): May 6, 2015

Study Record Updates

• Last Update Posted (Actual): September 16, 2020
• Last Update Submitted That Met QC Criteria: August 31, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Myelofibrosis; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Idelalisib
• Other Study ID Numbers: GS-US-397-1245

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No