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

• ClinicalTrials.gov Identifier: NCT03517137
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2018
• Last Update Posted: May 5, 2022
• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Information provided by (Responsible Party): European Organisation for Research and Treatment of Cancer - EORTC

Tracking Information

• First Submitted Date: April 5, 2018
• First Posted Date: May 7, 2018
• Last Update Posted Date: May 5, 2022
• Actual Study Start Date: August 1, 2019
• Estimated Primary Completion Date: August 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 24, 2018)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 24, 2018)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Very Early PET-response Adapted Targeted Therapy for Advanced Hodgkin Lymphoma: a Single -Arm Phase II Study
• Official Title: Very Early PET-response Adapted Targeted Therapy for Advanced Hodgkin Lymphoma: a Single -Arm Phase II Study
• 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.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Hodgkin Lymphoma

Intervention

• 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.

Study Arms

Experimental: Treatment

Interventions:

• Drug: Brentuximab Vedotin
• Drug: Adriamycin
• Drug: Vinblastine
• Drug: Dacarbazine
• Drug: Etoposide
• Drug: Cyclophosphamide
• Radiation: Radiation Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 24, 2018): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 1, 2023
• Estimated Primary Completion Date: August 28, 2023 (Final data collection date for primary outcome measure)

Eligibility 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Denmark, Netherlands, Poland, Portugal, Slovakia, Spain
• Removed Location Countries: Croatia, Egypt

Administrative Information

• NCT Number: NCT03517137
• Other Study ID Numbers: EORTC-1537-LYMG
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
• Original Responsible Party: Same as current
• Current Study Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Martin Hutchings; Past Chair EORTC Lymphoma Group
• Principal Investigator: Wouter Plattel; Active Member EORTC Lymphoma Group

• PRS Account: European Organisation for Research and Treatment of Cancer - EORTC
• Verification Date: May 2022