Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of brentuximab vedotin that can be combined with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin lymphoma that has come back (relapsed) or is not responding to treatment (refractory). Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells. Chemotherapy drugs, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving brentuximab vedotin together with an ifosfamide, carboplatin, and etoposide chemotherapy regimen may kill more cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. To determine maximally tolerated dose of brentuximab vedotin that can be combined with ifosfamide, carboplatin and etoposide chemotherapy in patients with relapsed or refractory Hodgkin lymphoma. II. To gain a preliminary assessment of the efficacy of the above regimen. SECONDARY OBJECTIVES: I. To determine the safety and toxicity of the above regimen. II. To determine the ability to proceed to peripheral blood stem cell collection following the above regimen (the impact of above regimen on stem cell reserve). III. To assess the impact of this regimen on biomarkers from the microenvironment in Hodgkin lymphoma tumors. OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study. Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on days 1 and 8; ifosfamide IV over 24 hours and carboplatin IV over 1 hour on day 2; and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients planning to go on to consolidative high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) may undergo peripheral blood stem cell (PBSC) mobilization following the 2nd course of study therapy at the discretion of the treating physician. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 4 years.
Interventions
DRUGBrentuximab Vedotin
Given IV
DRUGCarboplatin
Given IV
DRUGEtoposide
Given IV
DRUGIfosfamide
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
University of Washington
National Cancer Institute (NCI)
Seagen Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have primary refractory or first relapse of cluster of differentiation 30 (CD30)+ Hodgkin lymphoma * Patients must have measurable disease defined as lesions that can be accurately measured in two dimensions by computed tomography (CT), magnetic resonance imaging (MRI), medical photograph (skin or oral lesion), plain x-ray, or other conventional technique and a greatest transverse diameter of 1 cm or greater; or palpable lesions with both diameters \>= 2 cm; further, at least 1 of these lesions must be positive by positron emission tomography (PET) scan (i.e., Deauville score of 4 or more); Note: CT scans remain the standard for evaluation of nodal disease * Patients must have a CT of chest, abdomen, and pelvis with PET within 28 days of enrollment; patients with evidence of lymphadenopathy in the neck must have a dedicated CT of neck * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (performance status of 2 will be allowed if poor performance status is thought to be directly secondary to patient's Hodgkin lymphoma \[HL\]) * Absolute neutrophil count (ANC) \>= 1,500/uL, performed within 28 days prior to registration * Platelets \>= 100,000/uL (without transfusion or growth factor support), performed within 28 days prior to registration * Serum creatinine \< 1.5 mg/dl or creatinine clearance (CrCl) \> 60 mL/min, performed within 28 days prior to registration * Total bilirubin \< 2 times upper limit of normal (unless due to Gilbert's syndrome), performed within 28 days prior to registration * Aspartate aminotransferase (AST) \< 2.5 times upper limit of normal, performed within 28 days prior to registration * All patients must be informed of the investigational nature of this study and have given written consent in accordance with institutional and federal guidelines * Patients must be anticipated to complete 2 cycles of chemotherapy
Exclusion criteria
* Patients known to be positive for human immunodeficiency virus (HIV) * Pregnant or nursing women; men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method * Patients with other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in situ, or other cancer from which the patient has been disease-free for 5 years or greater, unless approved by the protocol chair or co-chair * Patients with known allergy, intolerance, or resistance (i.e., remission duration less than 6 months or lack of response) to ifosfamide, carboplatin, or etoposide * Patients with evidence of active central nervous system lymphoma * Patients with prior receipt of brentuximab vedotin * Patients with peripheral neuropathy of \> grade 1 * Patients who have other medical conditions that would contraindicate treatment with aggressive chemotherapy (including active infection, uncontrolled hypertension, congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or uncontrolled arrhythmia); if the patient's cardiac history is questionable, a measurement of left ventricular ejection fraction should be obtained within 42 days prior to registration; patients with left ventricular ejection fraction \< 50% are not eligible * Prior failed (\< 5 x 10\^6 CD34/kg) peripheral blood stem cell (PBSC) collection * Patients who had pelvic radiation within 12 months * Previous chemotherapy/immunotherapy within 3 weeks before study entry * Concurrent use of other anti-cancer agents or experimental treatments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Brentuximab Vedotin That Can be Combined With Ifosfamide, Carboplatin, and Etoposide Chemotherapy | Up to 28 days following the second course of chemotherapy, approximately 70 days | Will be defined as the dose at which =\< 1 of 6 patients experience a dose-limiting toxicity. Dose-limiting toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. |
| Percentage of Patients That Achieve a Complete Remission Following Study Treatment | 3 weeks following the completion of chemotherapy | — |
Secondary
| Measure | Time frame |
|---|---|
| 2 Year Overall Survival | Up to 2 years from initiation of study therapy. |
| 2 Year Progression-free Survival | Up to 2 years from initiation of therapy. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAjay Gopal
Fred Hutch/University of Washington Cancer Consortium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Dose Escalation, Dose Level 1 (Brentuximab 1.2mg/kg, Ifosfamide, Carboplatin, Etoposide) Patients receive brentuximab vedotin 1.2mg/kgIV over 30 minutes on days 1 and 8; ifosfamide IV over 24 hours and carboplatin IV over 1 hour on day 2; and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients planning to go on to consolidative HDT and ASCT may undergo PBSC mobilization following the 2nd course of study therapy at the discretion of the treating physician.
Brentuximab Vedotin: Given IV
Carboplatin: Given IV
Etoposide: Given IV
Ifosfamide: Given IV
Laboratory Biomarker Analysis: Correlative studies | 3 |
| Phase I: Dose Escalation, Dose Level 2 (Brentuximab 1.5mg/kg, Ifosfamide, Carboplatin, Etoposide) Patients receive brentuximab vedotin 1.5mg/kgIV over 30 minutes on days 1 and 8; ifosfamide IV over 24 hours and carboplatin IV over 1 hour on day 2; and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients planning to go on to consolidative HDT and ASCT may undergo PBSC mobilization following the 2nd course of study therapy at the discretion of the treating physician.
Brentuximab Vedotin: Given IV
Carboplatin: Given IV
Etoposide: Given IV
Ifosfamide: Given IV
Laboratory Biomarker Analysis: Correlative studies | 3 |
| Phase II: Dose Expansion (Brentuximab 1.5mg/kg, Ifosfamide, Carboplatin, Etoposide) Patients receive brentuximab vedotin 1.5mg/kgIV over 30 minutes on days 1 and 8; ifosfamide IV over 24 hours and carboplatin IV over 1 hour on day 2; and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients planning to go on to consolidative HDT and ASCT may undergo PBSC mobilization following the 2nd course of study therapy at the discretion of the treating physician.
Brentuximab Vedotin: Given IV
Carboplatin: Given IV
Etoposide: Given IV
Ifosfamide: Given IV
Laboratory Biomarker Analysis: Correlative studies | 39 |
| Total | 45 |
Baseline characteristics
| Characteristic | Phase I: Dose Escalation, Dose Level 1 (Brentuximab 1.2mg/kg, Ifosfamide, Carboplatin, Etoposide) | Phase I: Dose Escalation, Dose Level 2 (Brentuximab 1.5mg/kg, Ifosfamide, Carboplatin, Etoposide) | Phase II: Dose Expansion (Brentuximab 1.5mg/kg, Ifosfamide, Carboplatin, Etoposide) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 39 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 35 Participants | 41 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 | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 32 Participants | 38 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 39 participants | 45 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 27 Participants | 29 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 12 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 4 / 39 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 39 / 39 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 11 / 39 |
Outcome results
Primary
Maximum Tolerated Dose of Brentuximab Vedotin That Can be Combined With Ifosfamide, Carboplatin, and Etoposide Chemotherapy
Will be defined as the dose at which =\< 1 of 6 patients experience a dose-limiting toxicity. Dose-limiting toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Time frame: Up to 28 days following the second course of chemotherapy, approximately 70 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (brentuximab, ifosfamide, carboplatin, etoposide) | Maximum Tolerated Dose of Brentuximab Vedotin That Can be Combined With Ifosfamide, Carboplatin, and Etoposide Chemotherapy | 1.5 mg/kg |
Primary
Percentage of Patients That Achieve a Complete Remission Following Study Treatment
Time frame: 3 weeks following the completion of chemotherapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (brentuximab, ifosfamide, carboplatin, etoposide) | Percentage of Patients That Achieve a Complete Remission Following Study Treatment | 3 Participants |
| Phase I: Dose Escalation, Dose Level 2 (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | Percentage of Patients That Achieve a Complete Remission Following Study Treatment | 3 Participants |
| Phase II: Dose Expansion (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | Percentage of Patients That Achieve a Complete Remission Following Study Treatment | 26 Participants |
Secondary
2 Year Overall Survival
Time frame: Up to 2 years from initiation of study therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (brentuximab, ifosfamide, carboplatin, etoposide) | 2 Year Overall Survival | 3 Participants |
| Phase I: Dose Escalation, Dose Level 2 (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | 2 Year Overall Survival | 3 Participants |
| Phase II: Dose Expansion (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | 2 Year Overall Survival | 37 Participants |
Secondary
2 Year Progression-free Survival
Time frame: Up to 2 years from initiation of therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (brentuximab, ifosfamide, carboplatin, etoposide) | 2 Year Progression-free Survival | 2 Participants |
| Phase I: Dose Escalation, Dose Level 2 (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | 2 Year Progression-free Survival | 3 Participants |
| Phase II: Dose Expansion (brentuximab 1.5mg/kg, ifosfamide, carboplatin, etoposide) | 2 Year Progression-free Survival | 33 Participants |