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

Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:May 8, 2017
End Date:October 22, 2019

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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 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.


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.


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


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.


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

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

- 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

- 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

- History of allergy or adverse drug reaction to study components
We found this trial at
1100 Fairview Avenue North
Seattle, Washington 98109
(206) 667-5000
Principal Investigator: Ajay K. Gopal, MD
Phone: 206-288-2035
Fred Hutchinson Cancer Research Center At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of...
Seattle, WA
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Duarte, California 91010
Principal Investigator: Alex Herrera, MD
Phone: 626-256-4673
Duarte, CA
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Houston, Texas 77030
Principal Investigator: Michelle A. Fanale, MD
Phone: 713-792-2860
Houston, TX
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New Haven, Connecticut 6520
(203) 432-4771
Principal Investigator: Gottfried von Keudell, MD
Phone: 203-707-4257
Yale University Yale's roots can be traced back to the 1640s, when colonial clergymen led...
New Haven, CT
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