Clinical Trials /

Nivolumab, Ifosfamide, Carboplatin, and Etoposide as Second-Line Therapy in Treating Patients With Refractory or Relapsed Hodgkin Lymphoma

NCT03016871

Description:

This phase II trial studies the side effects of nivolumab and to see how well it works when given together with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin lymphoma that has come back and does not respond to treatment. Monoclonal antibodies, such as nivolumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, 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 nivolumab, ifosfamide, carboplatin and etoposide may work better in treating patients with Hodgkin lymphoma.

Related Conditions:
  • Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab, Ifosfamide, Carboplatin, and Etoposide as Second-Line Therapy in Treating Patients With Refractory or Relapsed Hodgkin Lymphoma
  • Official Title: A Phase II Trial of Response-Adapted Second-Line Therapy for Hodgkin Lymphoma Using Anti-PD-1 Antibody Nivolumab ± ICE Chemotherapy as a Bridge to Autologous Hematopoietic Cell Transplant (NICE Trial)

Clinical Trial IDs

  • ORG STUDY ID: 16403
  • SECONDARY ID: NCI-2016-02038
  • SECONDARY ID: 16403
  • NCT ID: NCT03016871

Conditions

  • CD (Cluster of Differentiation) 30-Positive Neoplastic Cells Present
  • Recurrent Hodgkin Lymphoma
  • Refractory Hodgkin Lymphoma
  • TNFRSF8 Positive

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (nivolumab, etoposide, ifosfamide, carboplatin)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (nivolumab, etoposide, ifosfamide, carboplatin)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Treatment (nivolumab, etoposide, ifosfamide, carboplatin)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, etoposide, ifosfamide, carboplatin)

Purpose

This phase II trial studies the side effects of nivolumab and to see how well it works when given together with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin lymphoma that has come back and does not respond to treatment. Monoclonal antibodies, such as nivolumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, 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 nivolumab, ifosfamide, carboplatin and etoposide may work better in treating patients with Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the anti-tumor activity of nivolumab as single agent and in combination with
      ifosfamide, carboplatin, etoposide (ICE) chemotherapy (nivolumab [N]ICE) as assessed by
      complete response (CR) rate prior to autologous hematopoietic cell transplantation.

      SECONDARY OBJECTIVES:

      I. Assess the safety and tolerability of nivolumab +/- ICE chemotherapy through evaluation of
      toxicities, including type, frequency, severity, attribution, time course and duration.

      II. Obtain estimates of overall response rate (ORR), response duration and survival (overall
      and event-free).

      III. Summarize stem cell mobilization outcomes (e.g., total CD34(cluster of differentiation
      34)+ cell yield, number of apheresis days, proportion of patients who achieve >= 2 x 10^6
      CD34+ cells/kg).

      IV. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab.

      V. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), estimate
      the post-AHCT overall/progression free survival (PFS) probability and cumulative incidence of
      relapse/progression, non-relapse mortality (NRM) at 100-days, 1-year and 2-years.

      VI. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),
      characterize post-AHCT toxicities during the first 30- and 100- days post stem cell infusion
      by type, frequency, severity, attribution, time course and duration.

      VII. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),
      evaluate short and long-term post-AHCT complications, including: delayed engraftment
      (neutrophil and platelet) and infection, graft versus host disease and sinusoidal obstruction
      syndrome.

      TERTIARY OBJECTIVES:

      I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and
      serial plasma samples for future biomarker evaluation.

      II. Evaluate potential changes in Hodgkin lymphoma biological markers of patients treated
      with nivolumab.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every
      14 days for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients
      with CR or partial response (PR) receive nivolumab for an additional 6 weeks. Patients with
      only stable disease (SD) after 6-week nivolumab treatment receive nivolumab for an additional
      6 weeks or receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3,
      ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2 every 21 days
      for 6 weeks per physician/investigator's discretion. Patients with progressive disease (PD)
      after 6-week nivolumab treatment or patients with PR, SD, or PD after 12-week nivolumab
      treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide
      IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every
      21 days for up to 2 courses 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 (nivolumab, etoposide, ifosfamide, carboplatin)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1. Courses repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients with CR or PR receive nivolumab for an additional 6 weeks. Patients with only SD after 6-week nivolumab treatment receive nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with PD after 6-week nivolumab treatment or patients with PR, SD, or PD after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Etoposide
  • Ifosfamide
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically documented or cytologically confirmed Hodgkin
             lymphoma; confirmation must include CD30 expression

          -  Patients must be either refractory to or relapsed after only induction therapy;
             patients who do not achieve CR after induction therapy are considered primary
             refractory and are allowed to enter study

          -  > 40 kg

          -  Absolute neutrophil count (ANC) >= 1500/uL (microliter); filgrastim can be given
             before and during treatment to achieve target ANC >= 1500 uL

          -  Platelet (Plt) >= 75,000/uL

          -  Hemoglobin >= 8.5 g/dl

          -  Platelet transfusion and packed red blood cell transfusion can also be given prior to
             the start of treatment and treatment to achieve a target plt >= 75,000/uL and
             hemoglobin of >= 8.5 g/dl, provided that patients have not received growth factors for
             at least 14 days prior to entering trial

          -  Patients must have measurable disease > 1.5 cm evidenced by computed tomography (CT)
             scan of the neck/chest/abdomen/pelvis or CT/positron emission tomography (PET) scans

          -  Life expectancy of greater than 3 months

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

          -  Documented informed consent/assent of the participant or legally responsible guardian

          -  Diffusion capacity of the lung for carbon monoxide (DLCO) >= 60%

          -  Total bilirubin with 1.5 x the upper limit of normal (ULN) institutional limits;
             patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are
             eligible

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x the
             institutional upper limit of normal (unless demonstrated Hodgkin lymphoma involvement
             of the liver)

          -  For patients with Hodgkin lymphoma (HL) involvement of the liver, AST/ALT < 5.0 x
             institutional ULN; total bilirubin within 3.0 x institutional ULN

          -  Estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault) and/or 24 urine analysis
             as needed

          -  Prothrombin time (PT)/international normalized ration (INR) < 1.5 x ULN and partial
             thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN

          -  Female subject is either post-menopausal, surgically sterilized, or willing to use and
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study; women of childbearing potential (WOCBP) must have a negative
             serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
             within 24 hours prior to the start of nivolumab

          -  Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year; men receiving nivolumab and who are sexually
             active with WOCBP will be instructed to adhere to contraception for a period of 31
             weeks after the last dose of investigational product; women who are not of
             childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as
             azoospermic men do not require contraception

          -  All participants will undergo standard written informed consent procedures as dictated
             by the City of Hope Human Research Protections Office prior to performing any
             screening procedures that are not part of standard-of-care; informed consent will be
             obtained by the principal investigator, collaborating investigators, or other
             Institutional Review Board (IRB) designated personnel who will meet the training
             requirements established by the IRB; with the support of research personnel, he/she
             will explain the nature, duration, purpose of the study, potential risks, alternatives
             and potential benefits, and all other information contained in the informed consent
             document; in addition, they will review the experimental subject's bill of rights and
             the Health Insurance Portability and Accountability Act (HIPAA) research authorization
             form; prospective research participants will be informed that they may withdraw from
             the study at any time and for any reason without prejudice; prospective research
             participants will be afforded sufficient time to consider whether or not to
             participate in the research

          -  Patient must be either refractory to or relapsed after 1 line of therapy

          -  Prior radiation therapy is allowed

        Exclusion Criteria:

          -  Prior exposure to PD-1 or PD-L1 inhibitors is not allowed

          -  Must not have had second line chemotherapy for Hodgkin lymphoma

          -  Active autoimmune diseases requiring systemic treatments

          -  Vaccinated with live, attenuated vaccine within 4 weeks of first dose of study drug

          -  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

          -  Unwilling or unable to participate in all required study evaluations and procedures

          -  Unable to understand the purpose and risks of the study and to provide a signed and
             dated informed consent for (ICF) and authorization to use protected health information
             (in accordance with national and local subject privacy regulations)

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

          -  Patients may not be receiving any other investigational agents, or concurrent
             biological therapy, chemotherapy, or radiation therapy

          -  Patients must not have received prior chemotherapy or radiation for =< 3 weeks before
             study enrollment, or those who have not recovered from the adverse events due to
             agents administered more than 3 weeks earlier are excluded

          -  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 arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities; prior study entry, any
             electrocardiogram (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

          -  DLCO < 60%

          -  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

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration; inhaled or
             topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease

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

          -  Recent infection requiring systemic treatment that was completed =< 14 days before the
             first dose of study drug

          -  Active with hepatitis C virus (HCV) or hepatitis B virus (HBV), subjects who are
             positive for hepatitis B core antibody or hepatitis B surface antigen must have a
             negative polymerase chain reaction (PCR) result before enrollment, those who are PCR
             positive will be excluded; subjects who have an undetectable human immunodeficiency
             virus (HIV) viral load with CD (cluster of differentiation)4 >= 300 and are on highly
             active antiretroviral therapy (HAART) medication are allowed; previously treated
             hepatitis C patients are also allowed; as there is potential for hepatic toxicity with
             nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to
             hepatoxicity should be used with caution in patients treated with nivolumab-containing
             regimen

          -  History of allergy or adverse drug reaction to study components
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:CR rate autologous stem cell transplantation assessed by Lugano criteria
Time Frame:1 year after primary outcome is met
Safety Issue:
Description:Response rates will be calculated as the percent of evaluable patients that have confirmed CR by radiographic response including CT and/or PET scans; 95% Clopper Pearson confidence limits will be calculated for this estimate.

Secondary Outcome Measures

Measure:Non-relapse mortality (NRM)
Time Frame:From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post HCT
Safety Issue:
Description:The cumulative incidence of NRM will be calculated as competing risks using the method of Gooley et al.
Measure:ORR
Time Frame:From the time measurement criteria are for CR or PR (whichever is first recorded) until the first date that relapsed or progressive disease is objectively documented, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:OS (overall survival) of hematopoietic cell transplant (HCT)
Time Frame:From start of HCT treatment to time of death (due to any cause), assessed up to 2 years post HCT
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Overall survival
Time Frame:From start of 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.
Measure:PFS
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:PFS of HCT
Time Frame:From start of HCT treatment to time of progression or death, whichever occurs first, assessed up to 2 years post HCT
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Relapse/progression event
Time Frame:From start of HCT treatment, assessed up to 2 years post HCT
Safety Issue:
Description:The cumulative incidence of relapse/progression will be calculated as competing risks using the method of Gooley et al.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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