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

NCT03016871 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: 16403NCI-2016-02038
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 4

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.

Conditions

Recurrent Hodgkin Lymphoma; Refractory Hodgkin Lymphoma

Outcome Measures

Primary Outcomes (2)

• 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.

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

• 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.

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

Secondary Outcomes (6)

• Overall Response Rate

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

• Two-Year Overall Survival (OS) Rate

  2 years from start of treatment

• Two-Year Progression-Free Survival (PFS) Rate

  2 years from start of treatment

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

  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.

• Cumulative Incidence of Relapse/Progression at 2 Years

  2 years from start of treatment

Study Arms (2)

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)

EXPERIMENTAL

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; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

EXPERIMENTAL

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; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Interventions

Carboplatin DRUG

Given IV

Also known as: Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin); Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

Etoposide DRUG

Given IV

Also known as: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin); Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

Ifosfamide DRUG

Given IV

Also known as: 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

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin); Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

Laboratory Biomarker Analysis OTHER

Correlative studies

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin); Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Cohort A (nivolumab, etoposide, ifosfamide, carboplatin); Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (4)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• 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.

  PMID: 35316328 DERIVED

MeSH Terms

Conditions

Hodgkin Disease

Interventions

Carboplatin; Etoposide; Ifosfamide; Nivolumab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Alex Herrera
• Organization: City of Hope Medical Center

aherrera@coh.org

626-359-8111

Study Officials

• Alex F Herrera

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2017
• First Posted: January 11, 2017
• Study Start: April 24, 2017
• Primary Completion: January 30, 2024
• Study Completion: April 30, 2026
• Last Updated: October 20, 2025
• Results First Posted: October 9, 2024

Record last verified: 2025-10

Locations

US (4)