Brentuximab Vedotin as Frontline Therapy in Diffuse Large B-Cell Lymphoma

November 5, 2013
Tracey Regan

The Journal of Targeted Therapies in Cancer, October 2013, Volume 2, Issue 5

The efficacy and safety of adding the experimental agent brentuximab vedotin (Adcetris) to standard chemotherapy to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is being evaluated in a randomized, open-label phase II trial.

Nancy Bartlett, MD

The efficacy and safety of adding the experimental agent brentuximab vedotin (Adcetris) to standard chemotherapy to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is being evaluated in a randomized, open-label phase II trial.

Brentuximab vedotin is an antibody-drug conjugate (ADC) that binds with CD30, a protein expressed on the surface of lymphoma cells, to deliver a powerful cytotoxin. The study will combine brentuximab with R-CHOP, the standard frontline therapy for DLBCL, the most common form of non- Hodgkin lymphoma with more than 20,000 new cases per year.

The drug is among a number of novel therapies now being tested in conjunction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to improve outcomes for patients with high-risk, aggressive lymphoma, a subgroup for which current therapies help only half of patients.

“While patients with the most advanced disease have a 50/50 chance of survival, we hope to do better. There are now several trials like this one that are attempting to take the next step,” said Nancy Bartlett, MD, the Koman Chair in Medical Oncology at Washington University School of Medicine in St. Louis, Missouri, and the principal investigator for the trial. “The addition of R to CHOP about 10 years ago was the first major improvement in the treatment of DLBCL in nearly 30 years. The hope is that combining R-CHOP with other targeted agents with unique mechanisms of action may increase survival rates even further.”

“There are no biomarkers or screening tests for lymphoma, in contrast to tests such as PSA in prostate cancer, and mammogram and colonoscopy in breast and colon cancers,” Bartlett said. “Patients have symptoms such as swollen lymph nodes, abdominal pain and bloating, and they move quickly on to biopsies. This is an aggressive disease that you want to diagnose and treat as quickly as possible.”

To be eligible for the study, participants must be newly diagnosed and at high risk—defined as scoring a 3 or higher on the IPI Index, a prognostic tool consisting of five factors, including age over 60 years, poor performance status, extra nodal sites, stage 3 or 4 disease, and elevated levels of lactase dehydrogenase (LDH).

“How well DLBCL patients do depends on disease stage and other prognostic factors determined by the IPI Index. For young, early-stage patients with good lab reports, the cure rate is 90%. But if you have three, four, or five factors from the IPI Index, your chance of a cure with R CHOP is in the 55% to 60% range,” Bartlett said, adding that high-risk patients were selected for the trial as they are “more likely to benefit from new approaches.”

The trial will divide 50 patients between two arms. Half will receive brentuximab vedotin 1.8 mg/kg plus R-CHOP every 3 weeks for up to six cycles. The other half will receive 1.2 mg/kg brentuximab vedotin plus R-CHOP, on the same schedule.

“We’re looking for effectiveness, but also for side effects. One concern is that we’re mixing drugs that have never been combined before,” Bartlett said. “We’re combining two tubulin inhibitors— brentuximab vedotin and vincristine—which can both cause peripheral neuropathy. So we’ll see what happens if we use the two together. Will we see more neuropathy? Will there be less neuropathy at the lower dose of brentuximab vedotin with the same level of tumor activity? We need to tease out both of those questions.”

TABLE. A Phase 2 Study of Brentuximab Vedotin in Combination with Standard of Care Treatment (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP]) as Front-line Therapy in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

CLINICALTRIALS.GOV IDENTIFIER: NCT01844505

Primary outcome measure:

Complete remission rate over a time frame of up to 6 months; incidence of adverse events; incidence of laboratory abnormalities

Secondary outcome measures:

Objective response rate over a time frame of up to 6 months; progression-free survival over a time frame of up to approximately 4 years; overall survival over a time frame of up to approximately 4 years

Study start date:

August 2013

Estimated study completion date:

May 2017

Estimated enrollment:

50

Patients:

Adults 18 years or older

SELECTED INCLUSION CRITERIA:

Treatment-naïve patients with systemic de novo or transformed diffuse large B cell lymphoma or follicular non-Hodgkin lymphoma grade 3b

International Prognostic Index score ≥ 3

Stage IAX (bulk defined as single lymph node mass > 10 cm in diameter), IB-IV disease

Measurable disease of at least 1.5 cm

Eastern Cooperative Oncology Group performance status ≤ 2

No previous treatment for indolent lymphoma

No previous other primary malignancy that has not been in remission for 3 years

DOSAGES:

Arm A:

Brentuximab vedotin 1.2 mg/kg administered intravenously every 3 weeks for up to 6 cycles plus R-CHOP (rituximab 375 mg/m2every 3 weeks by IV infusion for up to 6 cycles; vincristine 1.4 mg/m2every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total); cyclophosphamide 750 mg/m2every 3 weeks by IV infusion for up to 6 cycles; prednisone 100 mg on days 1-5 of each 3-week cycle, orally for up to 6 cycles; doxorubicin 50 mg/m2every 3 weeks by IV infusion for up to 6 cycles

Arm B:

Brentuximab vedotin 1.8 mg/kg administered intravenously every 3 weeks for up to 6 cycles plus R-CHOP (rituximab 375 mg/m2every 3 weeks by IV infusion for up to 6 cycles; vincristine 1.4 mg/m2every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total); cyclophosphamide 750 mg/m2every 3 weeks by IV infusion for up to 6 cycles; prednisone 100 mg on days 1-5 of each 3-week cycle, orally for up to 6 cycles; doxorubicin 50 mg/m2every 3 weeks by IV infusion for up to 6 cycles

Adverse Effects:

The most common treatment-emergent adverse events observed in a previous phase II trial for patients with relapsed B-cell lymphoma who received single-agent brentuximab vedotin were neutropenia, fatigue, nausea, and diarrhea. The most common grade 3 or 4 adverse events in that trial were neutropenia (25% grade 3; 11% grade 4) and anemia (9% grade 3).

The primary outcome measures in the trial are complete remission rate up to six months, as well as the incidence of adverse events and laboratory abnormalities. Secondary endpoints include objective response rate (ORR) up to six months, progression- free survival for up to approximately four years, and overall survival over four years.

Bartlett said she was encouraged by results from an earlier phase II trial for relapsed B-cell lymphoma that included 44 patients who received single- agent brentuximab vedotin, including 25 with DLBCL. Among patients with DLBCL the ORR was 44% (11 of 25), including 20% complete remissions and 24% partial remissions.

The most common treatment-emergent adverse events were neutropenia (43%), fatigue (36%), nausea (34%), and diarrhea (32%). The most common Grade 3 or 4 adverse events were neutropenia (25% Grade 3; 11% Grade 4) and anemia (9% Grade 3).

“Of the two dozen DLBCL patients enrolled in that trial, between 40% and 45% had at least a partial remission, including, interestingly, those with very low levels of CD30 expression,” she said. “It was encouraging to see the drug’s activity in those patients. The drug was well tolerated, too, with manageable side effects.”

Of the current study, Bartlett noted, “This is a small trial and we won’t draw huge conclusions from it as we would if we were comparing the drug to R-CHOP alone. It will give us preliminary information— hypothesis-generating information. We will be looking at PET scans, and if the results look promising, we’ll decide if it’s worth pursuing this combination in a larger group of patients. We will want to know how much more peripheral neuropathy we see and how quickly it resolves.”

Enrollees are identified through customary testing for DLBCL—standard lab tests, LDH tests, organ CT and PET scans, and bone marrow biopsies. They are being offered a follow-up biopsy 24 to 72 hours after the first dose to assess the drug’s immediate impact.

In a departure from the earlier trial, patients enrolling in the current study are not required to be CD30-positive.

Eric Sievers, MD

“The hypothesis is that there may be CD30 expression at lower levels that we’re not detecting,” Bartlett said, noting that the drug was developed to combat diseases with known high levels of CD30, including Hodgkin lymphoma and ALCL, in which it is diagnostic. “Following that, the idea was to see if other cancers have CD30, and in DLBCL, 10% to 30% of patients express it although not at high levels on malignant cells. But in the earlier trial, we saw responses even in patients with no detectable levels, raising questions about whether it is somewhere else in the cell, other than on the surface, that tests are not picking up.”

Little is known to date about CD30’s role as a cancer driver. Rather, the protein was selected as a target for ADC development for the access it provides to cancer cells and because it is highly expressed on malignant cells but rarely on normal cells.

“[Brentuximab vedotin] is not a drug that targets a specific cellular pathway. Instead, it employs a surface antigen target approach. The thinking behind ADCs is to define a cancer population by cell surface antigen expression and concentrate cytotoxic agents where it matters, while sparing normal tissue,” said Eric Sievers, MD, senior vice president of Clinical Development for the drug’s maker, Seattle Genetics.

“In this case, CD30 is the target—the handle by which we latch onto the cancer cell with the antibody and then enter it like a Trojan horse to deliver the cytotoxic agent, auristatin, a synthetic compound modeled on dolastatin, a toxic chemical produced by the Indian Ocean sea hare.”

The FDA approved brentuximab vedotin two years ago to treat relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) under its Accelerated Review program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. It was the first new FDA-approved treatment for HL since 1977 and the first specifically indicated to treat ALCL.

The approval was based on the results from two single-arm studies in which the drug was used alone to treat patients with HL and ALCL. The primary endpoints of both trials were ORR—the percentage of patients who experienced complete or partial cancer shrinkage or disappearance after treatment. In the HL trial, 73% of patients achieved either a complete or partial response to the treatment, and on average responded to the therapy for 6.7 months. In the ALCL trial, 86% of patients experienced either a complete or partial response and responded on average for 13.2 months.

There are now approximately three dozen clinical trials evaluating the drug that are either planned or are actively recruiting patients. In the company’s large, global phase III clinical trials, ECHELON-1 and ECHELON-2, the drug is being tested as a frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), including in patients with sALCL and other types of peripheral T-cell lymphoma.

“From what we know, CD30 is mostly limited to lymphomas, with some interesting exceptions, including embryonal germ cell tumors, a form of testicular cancer, and possibly leukemias. That’s where our research is taking us,” Sievers said.