A Phase I Trial of Brentuximab Vedotin Plus MDR1 Inhibitors in Relapsed/Refractory Hodgkin Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Brentuximab Vedotin
- Conditions
- Recurrent Hodgkin Lymphoma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Dose-limiting toxicity
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of brentuximab vedotin and cyclosporine when given together with verapamil hydrochloride in treating patients with Hodgkin lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. Immunosuppressive therapies, such as cyclosporine, may improve bone marrow function and increase blood cell counts. Verapamil hydrochloride may increase the effectiveness of brentuximab vedotin by overcoming drug resistance of the cancer cells. Giving brentuximab vedotin, cyclosporine, and verapamil hydrochloride may work better in treating patients with Hodgkin lymphoma.
Detailed Description
PRIMARY OBJECTIVE: I. Evaluate the safety and tolerability of the combination of brentuximab vedotin (BV) plus MDR1 inhibitors cyclosporine (CsA)/verapamil hydrochloride (verapamil \[VRP\]). SECONDARY OBJECTIVES: I. Obtain estimates of overall response rate (ORR), complete response (CR) rate, and response duration in patients treated with the combination of BV plus CsA/VRP. II. Estimate overall and progression-free survival in patients treated with the combination of BV plus CsA/VRP. III. Characterize pharmacokinetics of plasma monomethyl auristatin E (MMAE) in cycle 1 (for expansion cohort only). OUTLINE: This is a dose-escalation study of brentuximab vedotin and cyclosporine. Patients receive cyclosporine orally (PO) twice daily (BID) on days 1-5, verapamil hydrochloride PO four times daily (QID) on days 1-5, and brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients who have not progressed are followed up every 6 months until disease progression, start of a new lymphoma therapy, 2 years post treatment, or study completion, whichever is earlier. Patients who progress are followed up periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- •All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent
- •Voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
- •Weight over 40 kg
- •Life expectancy of greater than 3 months
- •Patients must have histologically documented or cytologically confirmed Hodgkin lymphoma
- •Patient must have measurable disease \> 1.5 cm evidenced by computed tomography (CT) of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans
- •Be willing to provide tissue from a fresh core or excisional biopsy (performed as standard of care) of a tumor lesion prior to starting study therapy or from archival tissue of a biopsy that was performed after the most recent systemic therapy. Exception can be granted by the principal investigator (PI) if a biopsy is not feasible and/or safe
- •Patients must be either refractory to or relapsed after at least 1 line of therapy
- •Prior brentuximab vedotin is allowed; expansion cohort is defined as:
- •Expansion cohort: BV refractory: Patient who had prior exposure to BV, and either - achieved a best response of stable disease (SD) or progressive disease (PD) or - achieved a best response of complete response (CR)/PR but developed PD while on active BV treatment
Exclusion Criteria
- •Patients who are hematopoietic stem cell transplant candidates are excluded
- •Vaccinated with live, attenuated vaccines within 4 weeks of enrollment
- •Patients may be on steroids prior to initiation of treatment, provided that, by cycle 1 day 1, steroid use is tapered down to less than or equal to 20 mg/day of prednisone
- •Patients may not be receiving any other investigational agents, or concurrent biological therapy, chemotherapy, or radiation therapy
- •Active graft versus host disease (GVHD) or on immunosuppressive medication of GVHD
- •Recent infection requiring intravenous anti-infective treatment that was completed =\< 14 days before enrollment
- •Unresolved toxicities from prior anticancer therapy, defined as having resolved to Common Terminology Criteria for Adverse Events (CTCAE, version 4.03), grade 0 or 1, with the exception of alopecia
- •Baseline grade II peripheral neuropathy
- •Hypersensitivity to BV or history of allergic reaction attributed to compounds of similar chemical or biologic composition of BV
- •Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
Arms & Interventions
Treatment (cyclosporine, verapamil, brentuximab vedotin)
Patients receive cyclosporine PO BID on days 1-5, verapamil hydrochloride PO QID on days 1-5, and brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Brentuximab Vedotin
Treatment (cyclosporine, verapamil, brentuximab vedotin)
Patients receive cyclosporine PO BID on days 1-5, verapamil hydrochloride PO QID on days 1-5, and brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclosporine
Treatment (cyclosporine, verapamil, brentuximab vedotin)
Patients receive cyclosporine PO BID on days 1-5, verapamil hydrochloride PO QID on days 1-5, and brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacokinetic Study
Treatment (cyclosporine, verapamil, brentuximab vedotin)
Patients receive cyclosporine PO BID on days 1-5, verapamil hydrochloride PO QID on days 1-5, and brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Verapamil
Treatment (cyclosporine, verapamil, brentuximab vedotin)
Patients receive cyclosporine PO BID on days 1-5, verapamil hydrochloride PO QID on days 1-5, and brentuximab vedotin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Verapamil Hydrochloride
Outcomes
Primary Outcomes
Dose-limiting toxicity
Time Frame: Up to 21 days
Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Secondary Outcomes
- Complete response rate assessed by Cheson 2014 criteria(Up to 2 years)
- Duration of complete response(Up to 2 years)
- Overall response rate (complete response + partial response)(Up to 2 years)
- Duration of overall response(Up to 2 years)
- Overall survival(From start of protocol treatment to time of death (due to any cause), assessed up to 2 years)
- Incidence of adverse events assessed(Up to 2 years)
- Progression-free survival(From start of treatment to time of disease progression or death due to any cause, whichever occurs first, assessed up to 2 years)