Classical Hodgkin Lymphoma
Conditions
Brief summary
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).
Detailed description
This is an open-label, single-group, Phase I/II study of itacitinib in combination with everolimus in subjects with relapsed or refractory cHL. Phase I will evaluate the safety and tolerability of itacitinib when combined with everolimus in subjects with relapsed refractory cHL using a 3 + 3 design; Phase II will evaluate the efficacy of the combination in subjects with cHL at the dose determined in Phase I using a Simon 2-stage expansion design. Subjects may continue to receive study treatment for 2 years or until evidence of disease progression, unacceptable toxicity, inability to obtain commercial everolimus or consent withdrawal.
Interventions
DRUGItacitinib
A JAK 1 selective small molecule inhibitor
DRUGEverolimus
A mammalian target of rapamycin (mTOR) inhibitor
Sponsors
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Efficacy of Itacitinib in Combination With Everolimus | 2 Years | Evaluate the efficacy of itacitinib in combination with everolimus in subjects with relapsed or refractory cHL as demonstrated by complete response (CR) rate, defined as the percentage of subjects achieving CR as their best response. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJakub Svoboda, MD
University of Pennsylvania
Participant flow
Recruitment details
Study: 23 evaluable subjects. Phase I: 6 to 15 subjects enrolled (with at least 6 subjects treated at the recommended Phase II dose (RP2D)). The itacitinib starting dose is 300 mg once daily (QD). Depending on tolerability, the itacitinib dose could be increased to 400 mg QD or decreased to 200 mg QD. The everolimus dose will remain 5 mg QD for each cohort. Phase II: Additional subjects will receive the RP2D of itacitinib with everolimus as determined in Phase I.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Starting Dose) Itacitinib 300 mg once daily (QD) in combination with everolimus 5 mg QD. | 3 |
| Cohort -1 Itacitinib 200 mg once daily (QD) in combination with everolimus 5 mg QD. | 0 |
| Cohort 2 Itacitinib 400 mg once daily (QD) in combination with everolimus 5 mg QD. | 20 |
| Total | 23 |
Baseline characteristics
| Characteristic | Cohort 1 (Starting Dose) | Cohort -1 | Cohort 2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 20 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 0 Participants | 19 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 0 Participants | 16 Participants | 19 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 6 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 14 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 0 | 7 / 20 |
| other Total, other adverse events | 3 / 3 | 0 / 0 | 20 / 20 |
| serious Total, serious adverse events | 1 / 3 | 0 / 0 | 6 / 20 |
Outcome results
Primary
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, defined as the percentage of subjects achieving CR as their best response.
Time frame: 2 Years
Population: Efficacy will be assessed by CR rate, defined as the percentage of subjects achieving Complete Response (CR) as their best response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Starting Dose) | Phase II: Efficacy of Itacitinib in Combination With Everolimus | 33.3 percentage of subjects achieving CR |
| Cohort 2 | Phase II: Efficacy of Itacitinib in Combination With Everolimus | 25 percentage of subjects achieving CR |
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Duration of Response.
Time frame: 2 years
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Overall Response Rate (ORR).
Time frame: 2 years
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Overall Survival (OS).
Time frame: 2 years
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Partial Response (PR).
Time frame: 2 years
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Progression Free Survival (PFS).
Time frame: 2 years
Secondary
Determine the Efficacy of Itacitinib in Combination With Everolimus in Terms of Stable Disease (SD).
Time frame: 2 years