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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Advanced Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Brentuximab Vedotin
* Drug: Adriamycin
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Etoposide
* Drug: Cyclophosphamide
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br> | Drug: Brentuximab Vedotin<br>* 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)<br>Drug: Adriamycin<br>* 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)<br>Drug: Vinblastine<br>* 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)<br>Drug: Dacarbazine<br>* 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)<br>Drug: Etoposide<br>* 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)<br>Drug: Cyclophosphamide<br>* 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)<br>Radiation: Radiation Therapy<br>* Patients with residual lymphoma mass(es) showing metabolic activity of Deauville score 4 or 5 after completion of chemotherapy will be offered consolidation radiotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Progression-free survival (mPFS) | 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 | 4 years after start of first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a negative FDG-PET | 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. | 4 years after start of first patient in | 
| Progression-free survival (PFS) | Progression-free survival | 4 years after start of first patient in | 
| Overall survival | Overall survival | 4 years after start of first patient in | 
| Adverse events graded according to the National Cancer Institute Common Occurrence of Adverse Events | Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 | 4 years after start of first patient in | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced Hodgkin lymphoma, brentuximab vedotin, phase 2