Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma

Study Overview
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Brief Summary
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This trial will study two treatment combinations for classical Hodgkin lymphoma (cHL). This trial will find out if these two treatment combinations work to treat cHL. It will also find out what side effects occur. A side effect is anything the drug does besides treating cancer. This study will have three parts (Parts A, B, and C). The drugs used in Part A are a combination of targeted anticancer drug (brentuximab vedotin) and three chemotherapy drugs (doxorubicin, vinblastine, and dacarbazine). These four drugs are called A+AVD. Participants will be treated with granulocyte colony stimulating factor (G-CSF) following every dose of A+AVD for 6 cycles of treatment (12 doses). Part A will look at whether the A+AVD drug combination reduces the number of participants who experience the side effect of febrile neutropenia. Febrile neutropenia is a very low white blood cell count and a fever, which can be life threatening. Parts B and C will use drug combination of brentuximab vedotin, plus nivolumab, doxorubicin, and dacarbazine. These four drugs are called AN+AD. Parts B and C will study how well the drugs work to treat cHL and what side effects they cause.

Detailed Description
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This study will have three parts. Part A of the study is designed to evaluate the incidence of febrile neutropenia, efficacy, and dose intensity in participants with advanced stage classical Hodgkin lymphoma (cHL) receiving granulocyte colony stimulating factor primary prophylaxis (G-PP) administration during treatment with frontline A+AVD. In Part A, participants will be treated with granulocyte colony stimulating factor (G-CSF) following every dose of A+AVD for 6 cycles of treatment. Participants will be treated using institutional standard of care practices for the majority of treatment decisions. Part B is designed to evaluate the combination of brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) as frontline treatment in participants with advanced cHL. In Part B, participants will be given AN+AD combination for 6 cycles of treatment. This part of the trial will look at whether this combination of drugs is effective and tolerable in participants with Stage II with bulky mediastinal disease and Stage III or IV cHL. Part C is designed to evaluate AN+AD as frontline treatment in participants with early stage cHL. In Part C, participants will be given AN+AD combination for 4 cycles of treatment. This part of the trial will look at whether this combination of drugs is effective and tolerable in participants with Stage I or II cHL with non-bulky mediastinal disease.

Official Title
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Multiple Part Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma Subjects

Conditions
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Hodgkin Lymphoma

Intervention / Treatment
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* Drug: brentuximab vedotin
* Drug: doxorubicin
* Drug: vinblastine
* Drug: dacarbazine
* Drug: G-CSF
* Drug: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Treatment-naïve, classic Hodgkin lymphoma (cHL) participants Participants enrolling in Part A of the study must have Ann Arbor Stage III or IV disease Participants enrolling in Part B of the study must have Ann Arbor Stage I or II cH: with bulky mediastinal disease, or Stage III or IV Participants enrolling in Part C of the study must have Ann Arbor Stage I or II cHL without bulky disease Histologically confirmed cHL according to the current World Health Organization (WHO) Classification Bidimensional measurable disease as documented by PET/CT or CT imaging Age 12 years or older in the United States. For regions outside of the US, participants must 18 years or older. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Exclusion Criteria Nodular lymphocyte predominant HL History of another malignancy within 3 years of the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk or metastasis or death. Participants with nonmelanoma skin cancer, localized prostate cancer, or carcinoma in situ of any type are not excluded if they have undergone complete resection Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy within 4 weeks of the first study drug dose Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Active cerebral/meningeal disease related to the underlying malignancy Any active Grade 3 or higher viral, bacterial, or fungal infection within two weeks of the first dose of study drug (Grade 3 defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, NCI CTCAE Version 4.03) Current therapy with other systemic anti-neoplastic or investigational agents Planned consolidative radiotherapy (Parts B and C only) Active interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity (Parts B and C only) Grade 3 or higher pulmonary disease unrelated to underlying malignancy Documented history of idiopathic interstitial pneumonia or diffusing capacity of the lung for carbon monoxide <50% predicted History of a cerebral vascular event within 6 months of first dose of study drug Child-Pugh B or C hepatic impairment Grade 2 or higher peripheral sensory or motor neuropathy Participants with acute or chronic graft-versus-host-disease (GvHD) or receiving immunosuppressive therapy as treatment or as prophylaxis against GvHD Previous treatment with brentuximab vedotin Participants who are pregnant or breastfeeding Other serious condition that would impair the participant's ability to receive or tolerate the planned treatment and follow-up

Ages Eligible for Study
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Minimum Age: 12 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: A+AVD<br>Brentuximab vedotin (A) plus doxorubicin (+A), vinblastine (V), and dacarbazine (D) administered by intravenous (IV) infusion in participants with advanced stage classical Hodgkin lymphoma (cHL) during each treatment cycle. | Drug: brentuximab vedotin<br>* 1.2 mg/kg by IV infusion<br>* Other names: SGN-35;Drug: doxorubicin<br>* 25 mg/m^2 by IV infusion<br>Drug: vinblastine<br>* 6 mg/m^2 by IV infusion<br>Drug: dacarbazine<br>* 375 mg/m^2 by IV infusion<br>Drug: G-CSF<br>* Granulocyte colony stimulating factor (G-CSF) primary prophylaxis administered 24-36 hours after each dose of A+AVD<br>* Other names: pegfilgrastim;|
| Experimental: Part B: AN+AD<br>Brentuximab vedotin (A) plus nivolumab (N), doxorubicin (+A), and dacarbazine (D) administered separately by IV infusion in participants with Stage II bulky mediastinal disease and Stage III or IV cHL during each treatment cycle. | Drug: brentuximab vedotin<br>* 1.2 mg/kg by IV infusion<br>* Other names: SGN-35;Drug: doxorubicin<br>* 25 mg/m^2 by IV infusion<br>Drug: dacarbazine<br>* 375 mg/m^2 by IV infusion<br>Drug: nivolumab<br>* 240 mg by IV infusion<br>* Other names: Opdivo;|
| Experimental: Part C: AN+AD<br>Brentuximab vedotin (A) plus nivolumab (N), doxorubicin (+A), and dacarbazine (D) administered separately by IV infusion in participants with Stage I or II cHL with non-bulky mediastinal disease during each treatment cycle. | Drug: brentuximab vedotin<br>* 1.2 mg/kg by IV infusion<br>* Other names: SGN-35;Drug: doxorubicin<br>* 25 mg/m^2 by IV infusion<br>Drug: dacarbazine<br>* 375 mg/m^2 by IV infusion<br>Drug: nivolumab<br>* 240 mg by IV infusion<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Febrile Neutropenia (FN) Rate (Part A) | The FN rate is defined as the number of participants who experience treatment-emergent FN. | 7.5 months | 
| Complete Response (CR) Rate (Parts B and C) | CR rate at EOT is defined as the percentage of subjects with CR at EOT, according to the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016), in subjects with previously untreated cHL. | 7.8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Refractory Disease Rate (Part A) | The primary refractory disease rate is defined as the percentage of participants with less than complete response or relapse within 3 months of EOT, according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas | 10.2 months | 
| Complete Response Rate (Part A) | The complete response rate is defined as the percentage of participants with CR at EOT according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). | 7.2 months | 
| Physician-reported Progression Free Survival (PFS) (Part A) | The physician-reported PFS rate at 2 years is estimated based on Kaplan-Meier methodology. | 24 months | 
| Subsequent Anticancer Therapy Utilization Rate (Part A) | Number of participants with subsequent anticancer therapy | 33.8 months | 
| Actual Dose Intensity: Brentuximab Vedotin (Part A) |  | 6.5 months | 
| Actual Dose Intensity: Doxorubicin, Vinblastine, Dacarbazine (Part A) |  | 6.5 months | 
| Relative Dose Intensity (Part A) |  | 6.5 months | 
| Rate of Dose Reduction and Delays: Brentuximab Vedotin (Part A) |  | 6.5 months | 
| Rate of Dose Reduction and Delays: Doxorubicin (Part A) |  | 6.5 months | 
| Rate of Dose Reduction and Delays: Vinblastine (Part A) |  | 6.5 months | 
| Rate of Dose Reduction and Delays: Dacarbazine (Part A) |  | 6.5 months | 
| Incidence of Adverse Events (Parts B and C) |  | 8.9 months | 
| Incidence of Laboratory Abnormalities (Parts B and C) | Laboratory values were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.03). | 8.9 months | 
| Overall Response Rate (ORR) at EOT (Parts B and C) | ORR is defined as the proportion of participants with CR or partial response (PR) at EOT according to the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016) in subjects with previously untreated cHL. | 7.8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine, Nivolumab, Seattle Genetics