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Very Early PET-response Adapted Targeted Therapy for Advanced Hodgkin Lymphoma: a Single -Arm Phase II Study (COBRA)

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ClinicalTrials.gov Identifier: NCT03517137
Recruitment Status : Not yet recruiting
First Posted : May 7, 2018
Last Update Posted : May 7, 2018
Sponsor:
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:
The main objective of this trial is to assess whether treatment adaptation based on a very early FDG-PET/CT results in improved efficacy while minimizing treatment toxicity in advanced stage Hodgkin Lymphoma (HL) patients treated with brentuximab vedotin (BV)-containing regimens.

Condition or disease Intervention/treatment Phase
Advanced Hodgkin Lymphoma Drug: Brentuximab Vedotin Drug: Adriamycin Drug: Vinblastine Drug: Dacarbazine Drug: Etoposide Drug: Cyclophosphamide Radiation: Radiation Therapy Phase 2

Detailed Description:

This single-arm phase II study investigates the value of early FDG-PET-response adapted BV-based therapy for advanced HL. All patients will receive one cycle of BrAVD followed by an FDG-PET/CT. Patients with a negative early FDG-PET(Deauville score 1-3) will continue with five more BrAVD cycles (total six cycles) while patients with a positive FDG-PET should shift to six cycles of BrECADD.

The hypothesis is that the efficacy will be comparable to the efficacy of BEACOPPesc and BrECADD, while using the intensive chemotherapy regimen only for those patients who do not achieve a negative FDG-PET after one cycle.

The choice to assess the treatment sensitivity by PET after a single cycle of BrAVD is based on results from a recent international multicenter study comparing FDG-PET/CT after one and two cycles of ABVD chemotherapy in HL. There is no reason to suspect that FDG-PET1 should be less prognostic after BrAVD than after ABVD.

With this trial, the investigators believe they can add important information about the optimal treatment of BV-containing first-line treatment for advanced HL, and thus answer important therapeutic questions that are likely to otherwise remain unanswered even after the Echelon-1 and HD21 trials reach mature results. This relatively large single-arm phase II trial of 150 patients will allow a meaningful comparison with the BrAVD and BrECADD regimens based on modified progression-free survival (primary endpoint) and progression-free survival (secondary endpoint) respectively.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Very Early PET-response Adapted Targeted Therapy for Advanced Hodgkin Lymphoma: a Single -Arm Phase II Study
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : September 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Drug: Brentuximab Vedotin
For PET positive (score of 4-5 following Deauville Criteria) patients: Brentuximab vedotin is administered as an IV infusion over a period of 30 minutes at 1.8 mg/kg on day 1, every 3 weeks (6 cycles); For PET negative (score of 1-3 following Deauville Criteria) patients: Brentuximab vedotin is administered as an IV infusion over a period of 30 minutes at 1.2 mg/kg on day 1 and 15, every 4 weeks (5 cycles)

Drug: Adriamycin
For PET positive (score of 4-5 following Deauville Criteria) patients: Adriamycin is administered as an IV infusion over a period of 15 minutes at 40 mg/m² on day 2, every 3 weeks (6 cycles); For PET negative (score of 1-3 following Deauville Criteria) patients: Adriamycin is administered as an IV infusion over a period of 15 minutes at 25 mg/m² on day 1 and 15, every 4 weeks (5 cycles)

Drug: Vinblastine
For PET negative (score of 1-3 following Deauville Criteria) patients: Vinblastine is administered as an IV infusion over a period of 15 minutes at 6mg/m² on day 1 and 15, every 4 weeks (5 cycles)

Drug: Dacarbazine
For PET positive (score of 4-5 following Deauville Criteria) patients: Dacarbazine is administered as an IV infusion over a period of 60 minutes at 250 mg/m² on day 3 and 4, every 3 weeks (6 cycles); For PET negative (score of 1-3 following Deauville Criteria) patients: Dacarbazine is administered as an IV infusion over a period of 60 minutes at 375 mg/m² on day 1 and 15, every 4 weeks (5 cycles)

Drug: Etoposide
For PET positive (score of 4-5 following Deauville Criteria) patients: Etoposide is administered as an IV infusion over a period of 60 minutes at 150 mg/m² on day 2,3 and 4, every 3 weeks (6 cycles)

Drug: Cyclophosphamide
For PET positive (score of 4-5 following Deauville Criteria) patients: Cyclophosphamide is administered as an IV infusion over a period of 30 minutes at 1250 mg/m² on day 2, every 3 weeks (6 cycles)

Radiation: Radiation Therapy
Patients with residual lymphoma mass(es) showing metabolic activity of Deauville score 4 or 5 after completion of chemotherapy will be offered consolidation radiotherapy.




Primary Outcome Measures :
  1. Modified Progression-free survival (mPFS) [ Time Frame: 4 years after start of first patient in ]

    Modified PFS (mPFS) is defined as the time interval between the date of treatment start and the date of the first of:

    • Progressive disease (PD)
    • Start of new treatment for Classical Hodgkin Lymphoma (cHL) when not in Complete Response at the end of protocol treatment; in this case, the date of mPFS is the date of the FDG-PET/CT scan at the end of protocol treatment. Switching therapy prior to end of protocol treatment for reasons other than Progressive Disease is not considered an event for mPFS. "End of protocol treatment" refers to completion of the planned protocol treatment with no more than 1 missed cycle, including radiotherapy on PET positive lesions if administered
    • Death due to any cause


Secondary Outcome Measures :
  1. Proportion of patients with a negative FDG-PET [ Time Frame: 4 years after start of first patient in ]
    It will be assessed how many patients have a negative FDG-PET image when taken at the end of their first cycle of BrAVD. The BrAVD cycle lasts 4 weeks.

  2. Progression-free survival (PFS) [ Time Frame: 4 years after start of first patient in ]
    Progression-free survival

  3. Overall survival [ Time Frame: 4 years after start of first patient in ]
    Overall survival

  4. Adverse events graded according to the National Cancer Institute Common Occurrence of Adverse Events [ Time Frame: 4 years after start of first patient in ]
    Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Previously untreated, histologically proven classical Hodgkin lymphoma;
  • Staged by PET with diagnostic-quality CT (i.v. contrast).
  • Clinical stages according to Lugano 2014 and based on FDG/PET CT:

    • Stage IIB with large mediastinal mass > 1/3 max transverse diameter thorax and/or extranodal lesion(s)
    • Stage III - IV
  • Consent to participation in translational research:
  • Archival tumor tissue available (15 blank formalin fixed paraffin embedded tissue samples mounted on APES slides or a tissue block).
  • Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment.
  • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1 percent per year) when used consistently and correctly.
  • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
  • Absence of any medical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  • Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

  • Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of Progressive Multifocal Leukoencenphalopathy
  • Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
  • Sensory or motor peripheral neuropathy greater than or equal to grade 2 according to CTCAE version 4.0
  • Any of the following cardiovascular conditions or values:

within 6 months before registration:

  • A left-ventricular ejection fraction <50 percent (at registration)
  • New York Heart Association (NYHA) Class III or IV heart failure.
  • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • symptomatic coronary heart disease (stable angina pectoris is allowed)
  • severe uncontrolled hypertension within 2 years before registration
  • Myocardial infarction
  • Patients with poorly controlled diabetes mellitus (HbA1c > 7.5 percent or a fasting blood sugar > 200 mg/dL).
  • Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to registration.
  • Known HIV infection, chronic active hepatitis C, HBV positivity (HBsAg + patients; HBsAg -/HBcAb+/HBV DNA+ patients).

Note: HBsAg-/HBV DNA - patients are eligible; patients who are seropositive due to vaccination are eligible

  • Concomitant or previous malignancies within the past 5 years with the exception of adequately treated carcinoma in situ of the cervix , nonmelanoma skin cancer.
  • Previous treatment with anti CD30 antibodies
  • Known hypersensitivity to any excipient contained in Brentuximab Vedotin formulation and other study drugs. Refer to Summary Product Characteristics for list of excipients.
  • Concurrent anti-cancer treatment or use of any investigational agent(s)

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): NCT03517137


Contacts
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Contact: Tina Verschuere, PhD 003227741504 1537@eortc.be

Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
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Principal Investigator: Martin Hutchings Past Chair EORTC Lymphoma Group
Principal Investigator: Wouter Plattel Active Member EORTC Lymphoma Group

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT03517137     History of Changes
Other Study ID Numbers: EORTC-1537-LYMG
First Posted: May 7, 2018    Key Record Dates
Last Update Posted: May 7, 2018
Last Verified: April 2018

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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

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
advanced Hodgkin lymphoma
brentuximab vedotin
phase 2

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
Cyclophosphamide
Etoposide
Etoposide phosphate
Doxorubicin
Liposomal doxorubicin
Vinblastine
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Tubulin Modulators