Clinical trial NCT03517137: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Advanced Hodgkin Lymphoma
Keywords: advanced Hodgkin lymphoma
brentuximab vedotin
phase 2
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2018-05-07
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Modified Progression-free survival (mPFS)
timeFrame: 4 years after start of first patient in
Secondary outcomes:
measure: Proportion of patients with a negative FDG-PET
timeFrame: 4 years after start of first patient in
measure: Progression-free survival (PFS)
timeFrame: 4 years after start of first patient in
measure: Overall survival
timeFrame: 4 years after start of first patient in
measure: Adverse events graded according to the National Cancer Institute Common Occurrence of Adverse Events
timeFrame: 4 years after start of first patient in
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: ZNA Stuivenberg
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Copenhagen
country: Denmark
facility: University Hospitals Copenhagen - Rigshospitalet
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - Locatie AMC
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden-Zuid
city: Leidschendam
country: Netherlands
facility: Haaglanden Medisch Centrum (HMC) - Haaglanden MC - locatie Antoniushove
city: Nijmegen
country: Netherlands
facility: Radboudumc - Radboud University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Warsaw
country: Poland
facility: Maria Sklodowska Curie National Institute of Oncology - National Research Institute
city: Lisboa
country: Portugal
facility: Instituto Portugues De Oncologia - Francisco Gentil - Centro De Lisboa
city: Bratislava
country: Slovakia
facility: National Cancer Institute
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Duran i Reynals (Institut Catala D'Oncologia)
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
Study officials:
affiliation: Past Chair EORTC Lymphoma Group
name: Martin Hutchings
role: PRINCIPAL_INVESTIGATOR
affiliation: Active Member EORTC Lymphoma Group
name: Wouter Plattel
role: PRINCIPAL_INVESTIGATOR
References: