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Recurrent Hodgkin LymphomaPhase 2NCT03016871

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

A Phase 2 study testing Carboplatin, Etoposide and Ifosfamide in people with Recurrent Hodgkin Lymphoma and Refractory Hodgkin Lymphoma, run by City of Hope Medical Center at 4 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

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 (relapsed) and does not respond to treatment (refractory). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Carboplatin, Etoposide and Ifosfamide
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
78 participants
Where
4 sitesUnited States
Study dates
8 May 2017to 30 Apr 2027
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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; filgrastim can be given before and during treatment to achieve target ANC >= 1500 uL
  • Platelet (Plt) >= 75,000/uL
  • Hemoglobin >= 8.5 g/dl
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  • 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); estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault) and/or 24 urine analysis as needed
  • 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; (although patients with HL involvement of the liver are frequently excluded from trials, their liver function tests often improve after treatment; the studies that led to nivolumab approval did not reveal any increased signals of liver toxicities attributed to nivolumab)
  • 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
  • B symptoms at relapse
  • Extranodal disease at relapse
  • Primary refractory disease
  • Relapsed < 1 year after completion of frontline therapy
  • Have received brentuximab vedotin as initial therapy

Who cannot join

  • 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
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  • 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%; the clinical studies in support of accelerated approval for nivolumab in chronic (c)HL after failure of ASCT required DLCO > 60%; certain HL induction regimens have the potential for pulmonary toxicity, and nivolumab carries the potential of pneumonitis or other pulmonary toxicities
  • 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 because of the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued
  • Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug
  • Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; 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 HIV viral load with CD4 >= 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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • City of Hope Medical Center

    Duarte, California, 91010

  • M D Anderson Cancer Center

    Houston, Texas, 77030

  • Yale University

    New Haven, Connecticut, 06520

  • Fred Hutchinson Cancer Research Center

    Seattle, Washington, 98109

Other trials in United States

About this study

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)

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 (relapsed) and does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor 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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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.

II. To estimate the proportion of patients experiencing unacceptable adverse events. (Cohort B) III. To assess the safety and tolerability of nivolumab + ICE chemotherapy through evaluation of toxicities, including type, frequency, severity, attribution, time course, and duration. (Cohort B) IV. To obtain estimate of overall response rate (ORR), complete response rate, response duration and survival (overall and event-free). (Cohort B) V. Summarize stem cell mobilization outcomes (e.g., total CD34+ cell yield, number of apheresis days, proportion of patients who achieve >= 2 x 10^6 CD34+ cells/kg). (Cohort B) VI. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab. (Cohort B)

SECONDARY OBJECTIVES:

  1. 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+ 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.

  1. 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.

EXPLORATORY OBJECTIVES:

  1. 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 are sequentially assigned to 1 of 2 cohorts.

COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles 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 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day 1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients 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 3 cycles 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.

Being tested
Carboplatin, Etoposide, Ifosfamide, Laboratory Biomarker Analysis, Nivolumab
Medical subject headings
Hodgkin Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CarboplatinDrug

    Also called Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino

    Given IV

  • EtoposideDrug

    Also called Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar

    Given IV

  • IfosfamideDrug

    Also called Asta Z 4942, Asta Z-4942, Cyfos, Holoxan

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

Study groups in NCT03016871
Study groupRoleWhat they receive
Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1. Cycles 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 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Carboplatin; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Biological: Nivolumab
Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)ExperimentalPatients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day 1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients 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 3 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Carboplatin; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Complete Response Rate by Lugano Classification

    Complete response rates were calculated as the percent of evaluable patients that have confirmed complete response by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits were calculated for this estimate.

    Measured: From the initial treatment to the end of the treatment, up to 6 months.

  2. Number of Participants With Unacceptable Adverse Events

    Toxicities were assessed and reported using the Bearman (non-hematologic) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scales. Unacceptable toxicity in a given patient is defined as any non-hematologic or hematological grade 3/4 toxicity that did not resolve to a grade 1/2 within 14 days per NCI CTCAE v4.03 toxicity criteria and was considered at least possibly related to nivolumab and/or ICE, or any other regimen-related cause of death.

    Measured: From initial treatment to the end of the study, up to 77 months.

Secondary outcomes (6)

  1. Overall Response Rate

    Overall response rate was calculated as the percent of evaluable patients that have confirmed complete response or partial remission by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits were calculated for this estimate.

    Measured: From the initial treatment to the end of the treatment, up to 6 months.

  2. Two-Year Overall Survival (OS) Rate

    Overall survival (OS) is defined as the duration of time from start of study treatment to time of death (due to any cause). OS rate was estimated using the product-limit method of Kaplan and Meier. The event is death.

    Measured: 2 years from start of treatment

  3. Two-Year Progression-Free Survival (PFS) Rate

    Progression-free survival is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first. PFS rate was estimated using the product-limit method of Kaplan and Meier. The event is progression/relapse or death.

    Measured: 2 years from start of treatment

  4. Two-Year Progression-Free Survival Rate (Post Autologous Transplant)

    Progression-free survival (PFS) is defined as the duration of time from start of transplant to time of progression or death, whichever occurs first. PFS rate was estimated using the product-limit method of Kaplan and Meier. The event is post-transplant progression/relapse or death.

    Measured: From start of transplant to time of progression, death (due to any cause), or last contact, whichever comes first, assessed 2 years post-transplant, up to 3 years.

  5. Cumulative Incidence of Relapse/Progression at 2 Years

    The cumulative incidence of relapse/progression was calculated as competing risks using the method of Gooley et al. The event is relapse/progression. Deaths without relapse/progression are considered a competing risk.

    Measured: 2 years from start of treatment

  6. Non-relapse Mortality (NRM) at 2 Years

    The cumulative incidence of non-relapse mortality was calculated as competing risks using the method of Gooley et al. NRM is defined as death occurring in a patient from causes other than relapse or progression. Deaths from relapse/progression are considered a competing risk.

    Measured: 2 years from start of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jan 2017 (estimated)
  2. Study start8 May 2017
  3. Primary completion30 Jan 2024
  4. Study completion30 Apr 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
78 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03016871
Sponsor's protocol ID
16403
Other IDs
NCI-2016-02038, 16403
Status last verified
Oct 2026
First submitted
6 Jan 2017
Last updated
2 Nov 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Mei MG, Lee HJ, Palmer JM, Chen R, Tsai NC, Chen L, McBride K, Smith DL, Melgar I, Song JY, Bonjoc KJ, Armenian S, Nwangwu M, Lee PP, Zain J, Nikolaenko L, Popplewell L, Nademanee A, Chaudhry A, Rosen S, Kwak L, Forman SJ, Herrera AF. Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE. Blood. 2022 Jun 23;139(25):3605-3616. doi: 10.1182/blood.2022015423.

    PubMed 35316328

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Carboplatin, Etoposide and Ifosfamide in people with Recurrent Hodgkin Lymphoma and Refractory Hodgkin Lymphoma, run by City of Hope Medical Center at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 2 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Complete Response Rate by Lugano Classification (time frame: From the initial treatment to the end of the treatment, up to 6 months.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03016871, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2026.

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