Published in UAB Insight, Summer 2008
Therapy for Recurrent and Refractory Disease
The National Cancer Institute estimates 8220 new cases of Hodgkin lymphoma will be diagnosed during 2008. Although current therapies cure 75% of patients, an estimated 1350 people will die this year. The median age at diagnosis is 38 years; one third of patients are aged between 20 and 34 years. "These are young patients who have children and are in the midst of their careers," says UAB hematologist and oncologist Andres Forero, MD. "Treatment of recurrent and refractory Hodgkin lymphoma remains an unmet medical need," he says. "Recent research into monoclonal antibodies may provide novel treatment options."
Hodgkin lymphoma is characterized by the Reed-Sternberg cell, which expresses the CD30 antigen. "For years researchers have tried to develop a monoclonal antibody against CD30," Forero says. Seattle Genetics, a biotechnology company specializing in monoclonal antibody-based therapies for several types of lymphoma, has developed antibody-drug conjugate (ADC) technology that may halt tumor growth.
One such ADC named SGN-35 interferes with the growth of CD30-positive hematological tumors, including Hodgkin lymphoma and anaplastic large-cell lymphoma. SGN-35 is an anti-CD30 antibody joined by an enzyme cleavable linker to the cytotoxic agent monomethyl auristatin E (MMAE). The ADC binds to CD30 on the tumor cell surface and leaches into the cell. The enzymatic drug linker degrades and releases MMAE, which causes G2/M phase cell cycle arrest and apoptosis. In preclinical models SGN-35 resulted in complete tumor regression.
Phase 1 Trials
UAB is recruiting for a phase 1 trial of SGN-35 for relapsed or refractory CD30-positive hematologic malignancies. Candidates are those with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 who have failed systemic chemotherapy, have completed prior treatments, and have measurable disease of at least 10 mm. The ongoing multicenter dose escalation study has involved 29 participants with a median of five prior therapies. About 76% of patients had previous stem cell transplant; 89% had an ECOG grade 0 to 1 (low grade). SGN-35 dose levels ranged from 0.1 to 2.7 mg/kg in 2-hour outpatient infusions every 3 weeks. Those stable after two doses received additional doses.
At ≥1.2 mg/kg, 7 of 13 patients achieved partial remission and remain on therapy. Tumor reductions occurred in 11 of 13 patients. The most common related adverse events were fatigue, diarrhea, and cough. Enrollment continues at 2.7 mg/kg. "It is encouraging to achieve multiple objective responses in such a heavily pretreated population," says Forero, who recently presented this information at the 2008 American Society of Clinical Oncologists' annual meeting in Chicago.
A second phase 1 trial is evaluating escalating doses of SGN-35 administered weekly. Investigators plan to enroll 40 participants at multiple US centers. Candidates are those with CD30-positive hematologic malignancy who have failed systemic chemotherapy and have measurable disease of at least 1.5 mm.
After the monotherapy portion of the trial, researchers will test the antitumor activity of SGN-35 combined with the chemotherapeutic agent gemcitabine. A preclinical study found SGN-35 improved antitumor activity when combined with chemotherapeutic regimens such as gemcitabine (Brit J Haematol. 2008;142[1]:69-73).
A Patient's Perspective
Before doctors referred Sabrina Gilreath to UAB, she had tried every available treatment for Hodgkin lymphoma. "Nothing worked. I lived on my couch. I was weak and so tired I couldn't go anywhere," she says. "Now I feel like a normal person."
Physicians diagnosed the 33-year-old Georgia native with Hodgkin lymphoma in 2002. She underwent 20 rounds of radiation, but after 6 months a CT scan indicated disease recurrence. Gilreath started chemotherapy. "I tried every kind of chemo. Some types shrank the tumor, and for almost 5 years the lymphoma was stable. Then the chemo stopped working," she says.
Gilreath went to Atlanta for a bone marrow transplant, but her own stem cells would not work, and none of her sisters were a match. Doctors found a donor but there was only a 33% chance of success. "I couldn't take that chance," she says, "and while I was waiting I grew too weak for the transplant. A clinical trial was my last option, so I was referred to UAB."
At UAB Gilreath met hematologist and oncologist Andres Forero, MD, and volunteered for a phase 1 trial of SGN-35. This time the treatment worked. "For more than a year I have had more energy, and I feel like myself again," she says. Gilreath now is receiving the trial's maximum dose of SGN-35. Every 3 weeks she comes to UAB for a full day of treatment. "This treatment has given me a new lease on life. I feel like a new human being," she says.
FOR MORE INFORMATION:
Dr. Andres Forero
1.800.UAB.MIST
mist@uabmc.edu