Itacitinib + Everolimus in Hodgkin Lymphoma

An Open-Label Phase I/II Safety and Efficacy Study of Itacitinib In Combination With Everolimus In Subjects With Relapsed/Refractory Classical Hodgkin Lymphoma

This is an open-label, single-group, Phase I/II study of itacitinib in combination with everolimus in subjects with relapsed or refractory classical Hodgkin lymphoma (cHL).

Study Overview

• Status: Active, not recruiting
• Conditions: Classical Hodgkin Lymphoma
• Intervention / Treatment: Drug: Itacitinib; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Able to understand and voluntarily sign the informed consent form.
2. Aged 18 years or older at the time of signing the informed consent form.
3. Biopsy-proven diagnosis of relapsed classical Hodgkin lymphoma.
4. Measurable disease on imaging defined as at least one lesion that can be accurately measured in at least two dimensions by imaging (PET/CT, CT or MRI). Minimum measurement must be ≥ 15mm in the longest axis or ≥ 10mm in the short axis.

5. Relapsed or refractory disease (after at least 2 prior systemic therapies); patients must have relapsed after high-dose therapy with ASCT, or have been deemed ineligible for high-dose therapy with ASCT based upon the below criteria:

   • Patients that have either progressed after treatment with, be intolerant to, or are not a candidate for brentuximab and pembrolizumab or nivolumab. The reason for forgoing such therapies must be clearly documented.
   • Are not ASCT candidates due to chemo-resistant disease (unable to achieve CR or PR to salvage chemotherapy), advanced age (≥ 65 years of age), or any significant coexisting medical condition (renal, pulmonary, or hepatic dysfunction) likely to have a negative impact on tolerability of ASCT
6. Disease free of other malignancies for greater than or equal to 2 years with the exception of basal cell, squamous cell carcinomas of the skin, fully excised melanoma in situ, carcinoma in situ of the cervix or breast.
7. Performance status of ECOG 0-2 (Appendix 13.3).

8. Laboratory test results within these ranges (of note, patients who have cytopenias due to documented cHL involvement of the bone marrow may be considered for enrollment after discussion with the PI, Medical Director and Sponsor):

   • Absolute neutrophil count (ANC) > 1,000/µL
   • Platelet count > 75,000/µL
   • Serum creatinine < 2.0 mg/dL
   • Bilirubin < 2.0 × ULN unless bilirubin increase was due to Gilbert's disease. Further evaluation should be performed to confirm and document the origin of increase.
   • AST and ALT ≤ 2.5 × institutional upper limit of normal (ULN)
   • Fasting cholesterol ≤ 300 mg/dL AND fasting triglycerides ≤ 300 mg/dl. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication prior initiating study treatment.
9. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 72 hours prior to the first dose of itacitinib and must agree to use an effective contraception method during the study and for 6 months following the last dose of study drug; females of non-childbearing potential are those who are post-menopausal for more than 1 year or who have had a bilateral tubal ligation or hysterectomy. Female patients undergoing active fertility preservation therapy/egg harvesting which include hCG injections are expected to have mild elevation of hCG. These patients may be allowed to participate in the trial despite elevation of hCG after providing documentation of negative hCG prior the hCG injection and statement from her fertility specialist that they are not pregnant.
10. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of study drug.
11. Must be able to comply with the study and follow-up requirements.
12. Subject must have access to everolimus via insurance or self-pay.

Exclusion Criteria:

1. Unable to sign informed consent form.
2. Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking the investigational agents).

3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. For Example:

   • symptomatic congestive heart failure of New York Heart Association Class III or IV
   • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
   • severely impaired lung function with O2 saturation that is 88% or less at rest on room air
   • active (acute or chronic) or uncontrolled severe infections
   • condition requiring ongoing use of medications that are considered STRONG or MODERATE CYP3A4 inhibitors or inducers and P-gp substrates at study screening . However, those who require weak inhibitors/inducers can be enroll at discretion of the PI.
   • liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).
4. Has a history (within the past 12 months) of (non-infectious) pneumonitis requiring systemic steroids, or active pneumonitis.
5. Bilirubin < 3 × ULN in the presence of liver metastases or presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia)
6. Concurrent use of other anti-cancer agents or therapies during study treatment.
7. Use of any other experimental drug or therapy within 28 days of initiating treatment with the investigational agents.
8. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis C (HCV), or hepatitis B virus (HBV); patients who are seropositive because of hepatitis B virus vaccine are eligible.
9. Previous use of JAK1 inhibitor (itacitinib), or history of progression on everolimus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Itacitinib and everolimus	Drug: Itacitinib; A JAK 1 selective small molecule inhibitor; Other Names: INCB039110; Drug: Everolimus; A mammalian target of rapamycin (mTOR) inhibitor; Other Names: Afinitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Collection of dose-limiting toxicities of combination treatment with itacitinib and everolimus.	To evaluate dose-limiting toxicities (DLTs) of combination treatment with itacitinib and everolimus occurring up to and during Day 28 of Cycle 1, and to establish a recommended Phase II dose (RP2D) in subjects with relapsed or refractory cHL.	30 Days
Phase II: Efficacy of itacitinib in combination with everolimus	Evaluate the efficacy of itacitinib in combination with everolimus in subjects with relapsed or refractory cHL as demonstrated by complete response (CR) rate	2 Years

Secondary Outcome Measures

Outcome Measure	Time Frame
Determine the efficacy of itacitinib in combination with everolimus in terms of Complete Response (CR).	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of Overall Response Rate (ORR).	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of Partial Response (PR).	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of Stable Disease (SD).	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of duration of response.	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of progression free survival (PFS).	2 years
Determine the efficacy of itacitinib in combination with everolimus in terms of overall survival (OS).	2 years

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Jakub Svoboda, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: September 28, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 5, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: IRB # 831774; UPCC #45418

Drug and device information, study documents

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