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

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ClinicalTrials.gov Identifier: NCT03016871
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : June 26, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief 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). 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.

Condition or disease Intervention/treatment Phase
Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma Drug: Carboplatin Drug: Etoposide Drug: Ifosfamide Other: Laboratory Biomarker Analysis Biological: Nivolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 24, 2017
Estimated Primary Completion Date : June 22, 2021
Estimated Study Completion Date : June 22, 2021


Arm Intervention/treatment
Experimental: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
Patients 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.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Ifosfamide
Given IV
Other Names:
  • Asta 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-4942

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
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.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Ifosfamide
Given IV
Other Names:
  • Asta 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-4942

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Complete response rate autologous stem cell transplantation assessed by Lugano criteria [ Time Frame: 1 year after primary outcome is met ]
    Response rates will be 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 will be calculated for this estimate.

  2. Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 2 years ]
    Toxicity will be assessed and reported using the Bearman (non-hematologic) and Common Terminology Criteria for Adverse Events version 4.03 scales. Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: From the time measurement criteria are for complete response or partial response (whichever is first recorded) until the first date that relapsed or progressive disease is objectively documented, assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  2. Overall survival [ Time Frame: From start of treatment to time of death (due to any cause), assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  3. Progression free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  4. Overall survival of hematopoietic cell transplantation [ Time Frame: From start of hematopoietic cell transplantation treatment to time of death (due to any cause), assessed up to 2 years post hematopoietic cell transplantation ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  5. Progression free survival of hematopoietic cell transplantation [ Time Frame: From start of hematopoietic cell transplantation treatment to time of progression or death, whichever occurs first, assessed up to 2 years post hematopoietic cell transplantation ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  6. Relapse/progression event [ Time Frame: From start of hematopoietic cell transplantation treatment, assessed up to 2 years post hematopoietic cell transplantation ]
    The cumulative incidence of relapse/progression will be calculated as competing risks using the method of Gooley et al.

  7. Non-relapse mortality [ Time Frame: From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post hematopoietic cell transplantation ]
    The cumulative incidence of non-relapse mortality will be calculated as competing risks using the method of Gooley et al.


Other Outcome Measures:
  1. Role of PDL1/L2, CD68 on lymphoma specimens [ Time Frame: Up to 2 years ]
    Summarized using standard descriptive methods.

  2. Role of T/B/natural killer cell subsets in the peripheral blood [ Time Frame: Up to 2 years ]
    Summarized using standard descriptive methods.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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; 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); 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
  • INCLUSION CRITERIA FOR COHORT B:
  • 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

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%; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016871


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Alex F. Herrera    626-256-4673 ext 82405    aherrera@coh.org   
Principal Investigator: Alex F. Herrera         
United States, Connecticut
Yale University Not yet recruiting
New Haven, Connecticut, United States, 06520
Contact: Iris Isufi    203-737-5751    iris.isufi@yale.edu   
Principal Investigator: Iris Isufi         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Hun J. Lee    713-794-1829    hunlee@mdanderson.org   
Principal Investigator: Hun J. Lee         
United States, Washington
Fred Hutchinson Cancer Research Center Not yet recruiting
Seattle, Washington, United States, 98109
Contact: Ajay K. Gopal    206-288-2035    agopal@u.washington.edu   
Principal Investigator: Ajay K. Gopal         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Alex F Herrera City of Hope Medical Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03016871    
Other Study ID Numbers: 16403
NCI-2016-02038 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16403 ( Other Identifier: City of Hope Medical Center )
First Posted: January 11, 2017    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carboplatin
Etoposide
Nivolumab
Etoposide phosphate
Ifosfamide
Isophosphamide mustard
Podophyllotoxin
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Antineoplastic Agents, Alkylating
Alkylating Agents
Keratolytic Agents
Dermatologic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators