Clinical Trials /

Brentuximab Vedotin, Cyclosporine, and Verapamil in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

NCT03013933

Description:

This phase I trial studies the side effects and best dose of brentuximab vedotin and cyclosporine when given together with verapamil in treating patients with Hodgkin lymphoma that has come back or does not respond to treatment. Monoclonal antibodies, such as brentuximab vedotin, may interfere with the ability of cancer cells to grow and spread. Immunosuppressive therapies, such as cyclosporine, may improve bone marrow function and increase blood cell counts. Verapamil may increase the effectiveness of brentuximab vedotin by overcoming drug resistance of the cancer cells. Giving brentuximab vedotin, cyclosporine, and verapamil may work better in treating patients with Hodgkin lymphoma.

Related Conditions:
  • Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Brentuximab Vedotin, Cyclosporine, and Verapamil in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma
  • Official Title: A Phase I Trial of Brentuximab Vedotin Plus MDR1 Inhibitors in Relapsed/Refractory Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 16414
  • SECONDARY ID: NCI-2016-02062
  • SECONDARY ID: 16414
  • NCT ID: NCT03013933

Conditions

  • Recurrent Hodgkin Lymphoma
  • Refractory Hodgkin Lymphoma
  • CD30-Positive Neoplastic Cells Present

Interventions

DrugSynonymsArms
Brentuximab VedotinADC SGN-35, Adcetris, Anti-CD30 Antibody-Drug Conjugate SGN-35, Anti-CD30 Monoclonal Antibody-MMAE SGN-35, Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35, cAC10-vcMMAE, SGN-35Treatment (cyclosporine, verapamil, brentuximab vedotin)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (cyclosporine, verapamil, brentuximab vedotin)
VerapamilVerapamil HydrochlorideTreatment (cyclosporine, verapamil, brentuximab vedotin)

Purpose

This phase I trial studies the side effects and best dose of brentuximab vedotin and cyclosporine when given together with verapamil in treating patients with Hodgkin lymphoma that has come back or does not respond to treatment. Monoclonal antibodies, such as brentuximab vedotin, may interfere with the ability of cancer cells to grow and spread. Immunosuppressive therapies, such as cyclosporine, may improve bone marrow function and increase blood cell counts. Verapamil may increase the effectiveness of brentuximab vedotin by overcoming drug resistance of the cancer cells. Giving brentuximab vedotin, cyclosporine, and verapamil may work better in treating patients with Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the safety and tolerability of the combination of brentuximab vedotin (BV) plus
      MDR1 inhibitors cyclosporine (CsA)/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 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 PO four
      times daily (QID) on days 1-5, and brentuximab vedotin intravenously (IV) over 30 minutes on
      day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cyclosporine, verapamil, brentuximab vedotin)ExperimentalPatients receive cyclosporine PO BID on days 1-5, verapamil 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.
  • Brentuximab Vedotin
  • Cyclosporine
  • Verapamil

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 with CD30 expression

          -  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

          -  Patients must be either refractory to or relapsed after at least 1 line of therapy

          -  Prior brentuximab vedotin is allowed; expansion cohorts are 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

          -  Eastern Cooperative Oncology Group (ECOG) performance score of 0-2

          -  Prior chemotherapy or radiation therapy is allowed if received >= 3 weeks before study
             enrollment

          -  Prior hematopoietic transplantation is allowed (autologous and/or allogeneic)

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3; filgrastim can be given prior to
             enrollment to achieve target ANC >= 1000/uL (to be performed within 10 business days
             prior to day 1)

          -  Platelets >= 50,000/mm^3; NOTE: platelet transfusion and packet red blood cell
             transfusion can be given prior to enrollment to achieve a target platelet (Plt) >=
             50,000/uL and hemoglobin of >= 8.5 g/dL (to be performed within 10 business days prior
             to day 1)

          -  Hemoglobin >= 8.5 g/dL (to be performed within 10 business days prior to day 1)

          -  Total bilirubin within 1.5 x the upper limit of normal institutional limits; patients
             with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible
             (to be performed within 10 business days prior to day 1)

          -  Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) unless
             demonstrated Hodgkin lymphoma involvement of the liver (to be performed within 10
             business days prior to day 1)

          -  Alanine aminotransferase (ALT) =< 3 x ULN unless demonstrated Hodgkin lymphoma
             involvement of the liver (to be performed within 10 business days prior to day 1)

          -  Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula and/or 24 hour
             (hr) urine analysis as needed (to be performed within 10 business days prior to day 1)

          -  If not receiving anticoagulants: international normalization ratio (INR) OR
             prothrombin (PT) =< 1.5 x ULN; if on anticoagulant therapy: PT must be within
             therapeutic range of intended use of anticoagulants

          -  If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x
             ULN; if on anticoagulant therapy: aPTT must be within therapeutic range of intended
             use of anticoagulants (to be performed within 10 business days prior to day 1)

          -  Female of childbearing potential: negative urine or serum pregnancy test; if the urine
             test is positive or cannot be confirmed as negative, a serum pregnancy test will be
             required (to be performed within 10 business days prior to day 1)

          -  In patients who are to receive VRP, base systolic blood pressure (SBP) > 110;
             diastolic blood pressure (DBP) > 60 and baseline heart rate > 60 (to be performed
             within 10 business days prior to day 1)

          -  Cardiac function (12 lead-electrocardiography [ECG] vs non 12 lead ECG) shows no
             underlying arrhythmia or heart blocks (for VRP only) (to be performed within 10
             business days prior to day 1)

          -  Female subjects must be either post-menopausal, surgically sterilized, or willing to
             use an acceptable method of birth control (i.e. a hormonal contraceptive,
             intra-uterine deice, diaphragm with spermicide, condom with spermicide, or abstinence)
             beginning prior to study entry, for the duration of the study, and for six months
             following duration of study participation; should a woman become pregnant or suspect
             that she is pregnant while participating on the trial, she should inform her treating
             physician immediately

          -  Male subjects must agree to use an acceptable method of contraception beginning prior
             to study entry, for the duration of the study, and for six months following duration
             of study participation

        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 not 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 to 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

          -  Patients should not have any uncontrolled illness including ongoing or active
             infection

          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in
             the investigator's opinion, could compromise the subject's safety or put the study
             outcomes at undue risk

          -  Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmia, or electrocardiograph evidence of acute ischemia
             or active conduction system abnormalities; prior to study entry, and ECG abnormality
             at screening has to be documented by the investigator as not medically relevant

          -  Significant screening electrocardiogram (ECG) abnormalities including, but not limited
             to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd
             degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac
             pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are
             considered not clinically significant as documented via a cardiology evaluation

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

          -  Patients with active central nervous system (CNS) disease or history of brain
             metastases are excluded from study

          -  Known active human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or
             hepatitis B virus (HBV) infection; subjects who have an undetectable HIV viral load
             with CD4 >= 200 and are on highly active antiretroviral therapy (HAART) medication are
             allowed; subjects who are positive for hepatitis B core antibody or hepatitis B
             surface antigen mush have a negative polymerase chain reaction (PCR) results before
             enrollment; those who are PCR positive will be excluded; patients who have had
             hepatitis C but have finished treatment and are PCR negative will be allowed (testing
             to be done only in patients suspected of having infections or exposures)

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued

          -  Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns with clinical
             study procedures

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)

          -  Unable to understand the purpose and risks of the study and to provide a signed and
             dated informed consent form (ICF) and authorization to use protected health
             information (in accordance with national and local subject privacy regulations)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:15 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity assessed by National Cancer Institute (NCI) CTCAE version 4.03
Time Frame:Up to 21 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Complete response rate assessed by Cheson 2014 criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated with the 95% exact binomial confidence interval and using the product-limit method of Kaplan and Meier along with Greenwood estimator of standard error.
Measure:Duration of complete response
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with Greenwood estimator of standard error.
Measure:Duration of overall response
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with Greenwood estimator of standard error.
Measure:Incidence of adverse events assessed by NCI CTCAE v4.03
Time Frame:Up to 2 years
Safety Issue:
Description:Observed toxicities will be summarized by type, severity, date of onset, duration, reversibility, and attribution.
Measure:Overall response rate (complete response + partial response) assessed by Cheson 2014 criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated with the 95% exact binomial confidence interval.
Measure:Overall survival
Time Frame:From start of protocol treatment to time of death (due to any cause), assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with Greenwood estimator of standard error.
Measure:Progression-free survival
Time Frame:From start of treatment to time of disease progression or death due to any cause, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with Greenwood estimator of standard error.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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