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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03517137

Collaborator

(none)

150

Enrollment

Locations

Arm

Anticipated Duration (Months)

7.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

150 participants

Allocation:

N/A

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

Actual Study Start Date :

Aug 1, 2019

Anticipated Primary Completion Date :

Aug 28, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Modified Progression-free survival (mPFS) [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

Proportion of patients with a negative FDG-PET [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) [4 years after start of first patient in]
Progression-free survival
Overall survival [4 years after start of first patient in]
Overall survival
Adverse events graded according to the National Cancer Institute Common Occurrence of Adverse Events [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZNA Stuivenberg	Antwerp	Belgium	2060
2	Cliniques Universitaires Saint-Luc	Brussels	Belgium	1200
3	Universitair Ziekenhuis Antwerpen	Edegem	Belgium	2650
4	U.Z. Leuven - Campus Gasthuisberg	Leuven	Belgium	3000
5	University Hospitals Copenhagen - Rigshospitalet	Copenhagen	Denmark	2100
6	Amsterdam UMC - Locatie AMC	Amsterdam	Netherlands	1105
7	Deventer Ziekenhuis	Deventer	Netherlands	7400
8	Medisch Spectrum Twente	Enschede	Netherlands	7500
9	University Medical Center Groningen	Groningen	Netherlands	9713
10	Medisch Centrum Leeuwarden-Zuid	Leeuwarden	Netherlands	8934
11	Haaglanden Medisch Centrum (HMC) - Haaglanden MC - locatie Antoniushove	Leidschendam	Netherlands	2262
12	Radboudumc - Radboud University Medical Center Nijmegen	Nijmegen	Netherlands	6525
13	Erasmus MC	Rotterdam	Netherlands	3015
14	Maxima Medisch Centrum - Locatie Veldhoven	Veldhoven	Netherlands	5500
15	Maria Sklodowska Curie National Institute of Oncology - National Research Institute	Warsaw	Poland	02781
16	Instituto Portugues De Oncologia - Francisco Gentil - Centro De Lisboa	Lisboa	Portugal	1099
17	National Cancer Institute	Bratislava	Slovakia	833
18	Hospital Duran i Reynals (Institut Catala D'Oncologia)	L'Hospitalet De Llobregat	Spain	08908
19	Complejo Hospitalario de Navarra	Pamplona	Spain	31008