Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma

Phase 2TerminatedNCT03646123

Seagen Inc.255 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Interventions

brentuximab vedotinDRUG

1.2 mg/kg by IV infusion

doxorubicinDRUG

25 mg/m\^2 by IV infusion

vinblastineDRUG

6 mg/m\^2 by IV infusion

dacarbazineDRUG

375 mg/m\^2 by IV infusion

G-CSFDRUG

Granulocyte colony stimulating factor (G-CSF) primary prophylaxis administered 24-36 hours after each dose of A+AVD

nivolumabDRUG

240 mg by IV infusion

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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

Locations (76)

Los Angeles Cancer Network / Compassionate Care Research Group

Fountain Valley, California, United States

Rocky Mountain Cancer Centers - Aurora

Aurora, Colorado, United States

University of Colorado Health Memorial Hospital

Colorado Springs, Colorado, United States

Cancer Centers of Colorado - Denver

Denver, Colorado, United States

Poudre Valley Health System (PVHS)

Fort Collins, Colorado, United States

Outcomes

Primary Outcomes

Febrile Neutropenia (FN) Rate (Part A)

The FN rate is defined as the number of participants who experience treatment-emergent FN.

Time frame: 7.5 months

Complete Response (CR) Rate at EOT (Parts B and C)

CR rate at EOT is defined as the percentage of participants with CR at EOT, according to the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016), in participants with previously untreated cHL.

Time frame: 7.8 months

Secondary Outcomes

Number of Participants With Adverse Events of Clinical Interest (AECI) (Part A)

An adverse event (AE) was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with the treatment. Participants with peripheral neuropathy (PN) adverse events were summarized under AECI.

Time frame: Approximately up to 7.5 months

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

Time frame: 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).

Time frame: 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. The determination of antitumor activity will be based on response assessments made according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014).

Time frame: 24 months

Number of Participants With Subsequent Anticancer Therapy Utilization (Part A)

Number of participants with subsequent anticancer therapy have been reported in this outcome measure.

Time frame: 33.8 months

Actual Dose Intensity: Brentuximab Vedotin (Part A)

Time frame: 6.5 months

Actual Dose Intensity: Doxorubicin, Vinblastine, Dacarbazine (Part A)

Time frame: 6.5 months

Relative Dose Intensity (Part A)

Time frame: 6.5 months

Rate of Dose Reduction and Delays: Brentuximab Vedotin (Part A)

Time frame: 6.5 months

Rate of Dose Reduction and Delays: Doxorubicin (Part A)

Time frame: 6.5 months

Rate of Dose Reduction and Delays: Vinblastine (Part A)

Time frame: 6.5 months

Rate of Dose Reduction and Delays: Dacarbazine (Part A)

Time frame: 6.5 months

Incidence of Adverse Events (Parts B and C)

Time frame: 8.9 months

Incidence of Laboratory Abnormalities (Parts B and C)

Laboratory values were graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.03). As per NCI CTCAE version 4.03 grading, Grade 1 indicated mild or asymptomatic laboratory abnormalities, Grade 2 indicated moderate laboratory abnormalities, and Grade 3 indicated severe and 4 indicated life-threatening laboratory abnormalities.

Time frame: 8.9 months

Overall Response Rate (ORR) at EOT (Parts B and C)

ORR is defined as the percentage 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 participants with previously untreated cHL.

Time frame: Up to 7.8 months

Duration of Response (DOR) at End of Study (Parts B and C)

DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of tumor progression per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016) or death, whichever came first. Duration of response was only calculated for the subgroup of participants achieving a CR or PR. Participants without progression or death were censored on the date of the last radiological assessment of measured lesions. Kaplan-Meier method was used.

Time frame: Up to 51.1 months

Duration of Complete Response (DOCR) (Parts B and C)

DOCR was defined as the time from start of the first documentation of CR to the first documentation of tumor progression (per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016) or death, whichever came first. DOCR was calculated for the subgroup of participants achieving CR. Participants without progression or death were censored on the date of the last radiological assessment of measured lesions. Kaplan-Meier method was used.

Time frame: Up to 51.1 months

Event Free Survival (EFS) Rate (Parts B and C)

EFS was defined as the time from the start of study treatment to the first documentation of objective tumor progression, death due to any cause, or receipt of subsequent anticancer therapy to treat residual or progressive disease, whichever occurred first. The determination of antitumor activity will be based on objective response assessments made according to Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016). Participants without progression or death were censored on the date of the last radiological assessment of measured lesions. EFS rate was percentage of participants with EFS.

Time frame: Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42

PFS Rate (Parts B and C)

PFS was defined as the time from start of study treatment to first documentation of objective tumor progression or death. The determination of antitumor activity will be based on objective response assessments made according to Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation of LYRIC (Cheson 2016). Participants without progression or death were censored on the date of the last radiological assessment of measured lesions. Kaplan-Meier method was used.

Time frame: At months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 from the start of study treatment

Overall Survival (OS) Rate (Parts B and C)

OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. Kaplan-Meier method was used.

Time frame: At months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39 and 42 from the start of study treatment

Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma

Overview

Conditions

Interventions

Eligibility

Locations (76)

Outcomes

Primary Outcomes

Secondary Outcomes