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Bendamustine Hydrochloride

Rituximab

Brentuximab Vedotin

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Immunoconjugates

Brentuximab Vedotin in Combination with Bendamustine and Rituximab

Brentuximab vedotin IV over 30 minutes on day 1.Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Brentuximab

Bendamustine IV over 30-60 minutes on days 1-2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Bendamustine

Rituximab IV on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Daniel O. Persky, MD

This phase II trial studies how well brentuximab vedotin, bendamustine, and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Monoclonal antibody-drug conjugates, such as brentuximab vedotin, use antibody to target chemotherapy in cancer cells. Drugs used in chemotherapy, such as bendamustine, work in different ways to kill cancer cells. Monoclonal antibodies, such as rituximab, kill the cancer cells directly, but also harness the immune system to kill the cancer cells. Adding brentuximab to rituximab may improve response rates in CD30 positive, CD20 positive Relapsed Refactory NHL.

PRIMARY OBJECTIVES:

I. Complete response (CR) rate and overall response rate (ORR) for patients with relapsed aggressive high-risk non-Hodgkin lymphoma (NHL) treated with brentuximab vedotin, bendamustine and rituximab (S-BR).

SECONDARY OBJECTIVES:

I. To estimate 2-year progression-free survival (PFS). II. To evaluate rate of positron emission tomography (PET)-CR and correlation to 2 year PFS.

III. To evaluate the toxicity of six cycles of S-BR. IV. To evaluate mobilization, stem cell collection, engraftment in patients that proceed to salvage autologous stem cell transplant (ASCT).

SCIENTIFIC OBJECTIVES:

I. To evaluate percentage of tumor cells that are positive or negative for cluster of differentiation (CD)30 by immunohistochemistry (IHC), the subcellular location of CD30 (membrane or cytoplasmic only with absence of membrane expression), intensity of scoring, and correlating with clinical outcomes.

II. To evaluate gene expression profiling (GEP) by Nanostring Technology and comparing expression levels of target genes in CD30 membrane positive, CD30 cytoplasmic only positive or CD30 negative tumor cells.

III. To evaluate correlation between mutations identified through next generation sequencing (NGS) including ribonucleic acid (RNA) sequencing of the tumor transcriptome, and correlating to GEP and CD30 IHC, and correlating to clinical outcomes.

IV. To evaluate the levels of soluble CD30 at baseline and in response to treatment.

SCHEDULE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1, bendamustine IV over 30-60 minutes on days 1-2, and rituximab IV on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Brentuximab Vedotin, Bendamustine, and Rituximab in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Phase II Study of Brentuximab Vedotin in Combination With Bendamustine and Rituximab, in Patients With CD30 Positive, Relapsed or Refractory B Cell Non-Hodgkin Lymphoma (NHL)

Subcellular location or CD30 (membrane or cytoplasmic only), intensity of scoring, and association with progression-free survival will be evaluated. These relationships will be assessed using a Cox proportional hazards model. Expression levels of target genes based on CD30 location will be assessed using two sample independent t tests, with adjustment for multiple comparisons to protect the false discovery rate.

The relationship between mutations identified through next generation sequencing, gene expression profiling, CD30 IHC and progression-free survival will be assessed using a Cox proportional hazards models.

The complete response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval.

The overall response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval.

PFS will be estimated using the Kaplan-Meier estimate, with stratification by allogeneic stem cell transplantation status.

The complete response rate by PET/CT will be estimated with the 95% exact confidence interval.

The proportion of patients with treatment-emergent AEs will be tabulated, including by causality, seriousness, severity/grade, and whether the AE resulted in death or discontinuation of treatment.

Brentuximab vedotin pharmacokinetics in combination therapy will be measured and correlated to single agent data.

Spots Global Cancer Trial Database for high grade b cell lymphoma