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ANIMATE: Phase II Study of Nivolumab Monotherapy for Relapsed/Refractory Hodgkin Lymphoma (ANIMATE)

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ClinicalTrials.gov Identifier: NCT03337919
Recruitment Status : Recruiting
First Posted : November 9, 2017
Last Update Posted : December 21, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
University College, London

Brief Summary:
This is a single-arm, phase II, multi-centre study of the safety and efficacy of the PD-1 inhibitor, nivolumab, as second-line or third-line salvage therapy as a bridge to stem cell transplant (SCT) in relapsed/ refractory classical Hodgkin lymphoma patients not achieving a complete metabolic response (CMR) on FDG-PET-CT scan after 2 cycles of first or second line salvage therapy.

Condition or disease Intervention/treatment Phase
Hodgkin Lymphoma Drug: Nivolumab Phase 2

Detailed Description:

This is a single-arm, phase II, multi-centre study of the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor, nivolumab, as second-line or third-line salvage therapy, and in particular as a bridge to stem cell transplant (SCT) in relapsed/ refractory classical Hodgkin lymphoma patients not achieving a complete metabolic response (CMR) on fluorodeoxyglucose positron emission tomography (FDG-PET) scan post 2 cycles of first or second line salvage therapy.

Approximately 120 patients with relapsed/refractory classical Hodgkin lymphoma will be registered while undergoing first or second line salvage therapy (first line is preferred).

Patients will have a centrally reviewed PET CT scan after 2 cycles of the salvage therapy they are receiving (or 4 cycles if they are undergoing treatment with brentuximab vedotin). Those with complete metabolic response (CMR) on PET CT scan (Deauville score 1-3) will not be eligible for trial treatment. They will be followed up for trial data collection purposes, and further management will be at their treating clinician's discretion.

Patients achieving less than CMR on central review of FDG-PET (Deauville score 4-5) will be eligible to receive up to 8 x 2-weekly nivolumab infusions. 30 patients will be treated on the trial.

After 4 courses of nivolumab, patients will have an additional centrally reviewed PET-CT scan (PET4). Patients achieving CMR will stop trial treatment, and enter follow up. Further treatment will be at their clinician's discretion but is likely to be stem cell transplant (SCT).Patients with partial metabolic response (PMR) or stable disease (SD) on PET4 will receive a further 4 cycles of nivolumab, again followed by a centrally reviewed PET-CT scan (PET8) to assess final response.

Further management after PET8 will be at the discretion of the treating clinician, although it is anticipated that those with CMR or PMR will proceed to SCT. If PET8 shows less than CMR (i.e. PMR or SD), patients who consent will have a further biopsy to exclude false positive PET signal; this will be centrally reviewed.

Patients with progressive metabolic disease (PMD) on nivolumab at any point will stop trial treatment. If a repeat biopsy is obtained to confirm progressive disease histologically, the biopsy material will be centrally reviewed.

Patients will be followed up for a minimum of 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single-arm, phase II, multi-centre study. It will use an Ahern single stage design with independent trials steering committee review to monitor for safety and efficacy.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Nivolumab Monotherapy in Patients With Relapsed/Refractory Hodgkin Lymphoma Fit for Autologous Stem Cell Transplant Who Fail to Reach Complete Metabolic Remission After First or Second Line Salvage Therapy
Actual Study Start Date : December 3, 2018
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab
Up to 8 x 2-weekly cycles of nivolumab 240mg IV. Interim PET-CT scan to be performed after 4 cycles, and centrally reviewed. Patients will stop treatment after 4 cycles if they have complete metabolic response or progressive metabolic disease. If they have partial metabolic response or stable disease, they will continue to 8 cycles.
Drug: Nivolumab
Up to 8 cycles of nivolumab
Other Name: Opdivo®




Primary Outcome Measures :
  1. Overall response rate (ORR) by PET-CT scan following 4-8 cycles of nivolumab [ Time Frame: 4 months ]
    Rate of patients achieving complete metabolic response (CMR) on PET-CT scan following 4 or 8 cycles of nivolumab


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 1 year ]
    Progression-free survival at 1 year; also to be analysed stratified by partial metabolic response vs complete metabolic response.

  2. Overall survival [ Time Frame: 1 year ]
    Overall survival at 1 year; also to be analysed stratified by partial metabolic response (PMR) vs complete metabolic response (CMR).

  3. Proportion of patients progressing to stem cell transplant [ Time Frame: 1 year ]
    Proportion of patients progressing to autologous or allogeneic stem cell transplant

  4. Adverse events [Safety and toxicity of nivolumab] [ Time Frame: 3 years ]
    Adverse events and serious adverse events occurring in patients treated with nivolumab, in particular autoimmune toxicity

  5. Transplant-related mortality [ Time Frame: 3 years ]
    Proportion of patients treated with nivolumab that subsequently die of transplant-related causes

  6. Transplant-related morbidity [ Time Frame: 3 years ]
    Proportion of patients treated with nivolumab that go on to suffer serious complications of allogeneic transplant (grade 3-4 graft-versus-host disease, hyperacute graft-versus-host disease and steroid-responsive febrile syndrome)


Other Outcome Measures:
  1. Biopsy-negative PMR rate [ Time Frame: 4 months ]
    Correlation of PET positive disease with histological evidence of disease on post-treatment repeat biopsy to establish biopsy negative PMR rate (subject to patient consent)

  2. Serological biomarkers of response to nivolumab [ Time Frame: 5 months ]
    Correlation of disease response with serological markers such as serum Thymus and activation-regulated chemokine (TARC) levels

  3. Immunological biomarkers of response to treatment [ Time Frame: 4 months ]
    Evaluate the correlation between response to nivolumab and biological parameters e.g. PD-L1 expression on Reed Sternberg cells



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:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria for study registration:

  1. Age 16 or over
  2. Primary refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma in first relapse
  3. About to receive, or within 14 days of receiving first 2 cycles of first or second line salvage therapy (4 cycles if receiving treatment with brentuximab vedotin)
  4. Fit for autologous stem cell transplantation
  5. Written informed consent
  6. Willing to comply with the contraceptive requirements of the trial

Exclusion criteria for study registration:

  1. Nodular lymphocyte predominant Hodgkin lymphoma
  2. Women who are pregnant or breastfeeding
  3. History of colitis, inflammatory bowel disease or pneumonitis
  4. Patients with autoimmune disorders, except patients with vitiligo, diabetes mellitus type 1, hypo- and hyperthyroidism not requiring immunosuppressive therapy
  5. Known history of hepatitis B or C infection
  6. Known HIV infection
  7. History of allergy (including severe/life threatening skin reaction) to monoclonal antibodies, anaphylaxis or uncontrolled allergy
  8. Major surgery within 4 weeks prior to registration
  9. Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within the past 6 months
  10. Non-haematological malignancy within the past 3 years (with some exceptions - listed in protocol)

Inclusion criteria for trial treatment:

  1. Has received 2 cycles of first or second line salvage chemotherapy, (4 cycles if receiving treatment with brentuximab vedotin)
  2. PET positive (Deauville score 4 or 5) after 2 cycles of first or second line salvage chemotherapy (4 cycles if receiving treatment with brentuximab vedotin)
  3. Fit for further salvage chemotherapy
  4. ECOG performance status 0-1
  5. Creatinine clearance >30ml/min calculated by Cockcroft-Gault formula
  6. Bilirubin <1.5 x ULN, ALT/AST <2.5 x ULN
  7. Adequate bone marrow function (Hb >80g/l, Platelets >50 x 10^9/l, neutrophils >1.0 x 10^9/l)

Exclusion criteria for trial treatment:

  1. Deauville score 1-3 after 2 cycles of first or second line salvage chemotherapy (4 cycles if receiving treatment with brentuximab vedotin)
  2. Positive serology for hepatitis B or C (unless due to vaccination)
  3. Active infection requiring systemic therapy
  4. Ongoing requirement for immunosuppressive therapy, apart from inhaled, intranasal, topical corticosteroids or systemic corticosteroids at low doses (≤10mg prednisolone per day, or the equivalent)
  5. Chemo- or radiotherapy or corticosteroids at a dose of more than 10mg per day prednisolone or equivalent within 14 days prior to response PET-CT. NOTE: corticosteroids can be used AFTER a positive PET-CT scan for symptomatic disease but must be weaned to a dose of prednisolone ≤10mg/day or less (or equivalent) at least 7 days prior to starting nivolumab.
  6. Treatment with any investigational agent within 28 days prior to planned start of nivolumab
  7. Ongoing grade 2-4 non-haematological toxicities related to prior Hodgkin lymphoma treatments, with the exception of alopecia and grade 2 fatigue
  8. Pregnant or breastfeeding women

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): NCT03337919


Contacts
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Contact: Oliver Schofield +44 (0)20 7679 9860 ctc.animate@ucl.ac.uk

Locations
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United Kingdom
Leicester Royal Infirmary Recruiting
Leicester, United Kingdom, LE1 5WW
Contact: Thomas Rogers    0116 258 5951    thomas.rogers@uhl-tr.nhs.uk   
Principal Investigator: Fiona Miall         
Churchill Hospital Recruiting
Oxford, United Kingdom, OX3 7LE
Contact: Reihaneh Emami    01865 235309    Trialadministrator07@oncology.ox.ac.uk   
Principal Investigator: Graham Collins         
Sponsors and Collaborators
University College, London
Bristol-Myers Squibb
Investigators
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Principal Investigator: Graham Collins Oxford University Hospitals NHS Trust

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03337919     History of Changes
Other Study ID Numbers: UCL/15/0515
CA-209-445 ( Other Grant/Funding Number: Bristol-Myers Squibb )
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Hodgkin Disease
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents