Results from two ongoing phase I clinical trials evaluating SGN-CD19A (Seattle Genetics), an antibody-drug conjugate or ADC in development for the treatment of B-cell malignancies, including non-Hodgkin lymphoma or NHL and acute lymphoblastic leukemia or ALL, were presented on Saturday during the 56th Annual Meeting and Exposition of the American Society of Hematology, being held December 6 – 9, 2014 in the Moscone Center in San Francisco, CA.[1][2]

Antibody-drug conjugates combine a target specific tumor-recognizing monoclonal antibody or mAb with a small molecule drug to deliver a chemotherapeutic agent directly to specifically targeted cancer cells. If compared with traditional small-molecule chemotherapy antibody-drug conjugates, including Seattle Genetics’ SGN-CD19A, limit the risk of cytotoxicity to non-cancerous cells. At the same time, ADCs enable use of more potent cytotoxic agents.

ASHSGN-CD19A targets CD19, a protein expressed broadly on B-cell malignancies. The trial drug is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cell-killing agent, monomethyl auristatin F (MMAF). The ADC is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

MabPlex
 

“Aggressive B-cell malignancies are difficult diseases to treat, especially in the second- and third-line settings,” said Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “The data presented at ASH from two ongoing phase 1 clinical trials demonstrate encouraging antitumor activity with SGN-CD19A in patients with recurrent diffuse large B-cell lymphoma and acute lymphoblastic leukemia. The activity and safety profile, particularly multiple objective responses observed without significant myelosuppression or neuropathy typically associated with cancer treatment, supports the evaluation of SGN-CD19A in combination with standard of care regimens in the relapsed diffuse large B-cell lymphoma setting where improved outcomes are urgently needed. We look forward to initiating a randomized phase II trial evaluating SGN-CD19A in this setting in 2015.”

Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and NHL. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of non-Hodgkin lymphoma. According to the American Cancer Society, more than 70,000 cases of non-Hodgkin lymphoma were to be diagnosed in the United States during 2014 and nearly 19,000 people would die from the disease.

Options to treat patients with relapsed or refractory Non-Hodgkin Lymphoma is limited.  Overall, approximately 40% of DLBCL patients dor not respond to salvage therapy [3] and approximately 80% of patients do not respond tethered line treatment following salvage therapy, with an OS of approximately 4 months. [4]

The researchers in this phase I study reported data from 52 patients with relapsed or refractory NHL, including 45 patients with diffuse large B-cell lymphoma (DLBCL), three patients with grade 3 follicular lymphoma and four patients with mantle cell lymphoma. Of the 52 patients, 30 patients (58%) were refractory to their last therapy and 22 patients (42%) were relapsed. Fourteen patients (27%) had received a prior autologous stem cell transplant.

The median age of patients was 65 years.

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of SGN-CD19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients receive SGN-CD19A on an every three week schedule.

Patients with stable disease or better are eligible to continue treatment with SGN-CD19A. Key findings in a poster presentation by Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, include:

  • The maximum tolerated dose was not exceeded after escalating to 6 milligrams per kilogram (mg/kg) every three weeks. In addition, evaluation of an every six week dosing schedule is underway and enrollment is ongoing.
  • Of the 51 patients evaluable for response, 18 patients (35%) achieved an objective response, including 10 patients (20%) with a complete remission and eight patients (16%) with a partial remission. Thirteen patients (25%) achieved stable disease and 20 patients (39%) had disease progression.
  • Antitumor activity appeared to be higher in relapsed patients. Of the 22 relapsed patients, 12 patients (55%) achieved an objective response, including seven patients (32%) with a complete remission and five patients (23%) with a partial remission. Six patients (27%) achieved stable disease and four patients (18%) had disease progression.

Adverse events
In this trial, the most common observed  adverse events of any grade occurring in more than 25% of patients were blurred vision (60%), dry eye (46%), fatigue (38%), constipation (33%) and keratopathy (31%). Most ocular symptoms were Grade 1/2. The majority of patients with Grade 3 or 4 ocular symptoms and/or corneal findings experienced improvement and/or resolution at last follow-up. Ocular symptoms and corneal findings were managed with steroid eye drop treatment and dose modifications.

Relapsed or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma
Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children. According to the American Cancer Society, approximately 6,000 people were diagnosed with ALL during 2014 and more than 1,400 died from the disease.

In this phase I trial, adult and pediatric patients with relapsed or refractory B-lineage ALL and highly aggressive lymphoma, including B-cell lymphoblastic lymphoma (LBL) and Burkitt lymphoma were enrolled. Data were reported from 51 adult patients. The median age of adult patients was 43 years and the median number of prior systemic therapies was two, with 14 patients (27%) having received a prior allogeneic stem cell transplant. The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of SGN-CD19A.

In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received SGN-CD19A at either 0.3 to 2.3 mg/kg weekly or 4 to 6 mg/kg every three weeks. Key findings presented by Amir Fathi, M.D., Massachusetts General Hospital, include:

  • At the time of data analysis, dose escalation is ongoing. Safety analysis included data from 51 patients, including 18 patients treated every three weeks and 33 patients treated weekly.
  • Of the 14 ALL and LBL adult patients evaluable for response treated every three weeks, five patients (36%) achieved an objective response, including four patients (29%) with a complete remission and one patient (seven percent) with a partial remission. Eight patients (57%) achieved stable disease and one patient (7%) had disease progression.
  • Of the 29 ALL and LBL adult patients evaluable for response treated with weekly dosing, six patients (20%) achieved an objective response, including five patients (17%) with a complete remission and one patient (three percent) with a partial remission. Ten patients (34%) achieved disease stabilization and 13 patients (45%) had disease progression.
  • The most common adverse events of any grade occurring in 25% or more of adult patients treated every three weeks (18 patients) and weekly (33 patients), respectively, were fever (56 and 55%), chills (33 and 56%), fatigue (33 and 55%), headache and nausea (28 and 55%), blurred vision (39 and 36%), vomiting (28 and 42%) and febrile neutropenia (28 and 33%).
  • Symptoms related to keratopathy were reported in 27 patients. All symptoms were Grade 1/2; no Grade 3 symptoms were reported. The most common symptoms were blurred vision, dry eye and photophobia. Grade 3 or 4 keratopathy was reported in 10 patients and the majority had experienced improvement and/or resolution at last follow-up. Ocular symptoms and corneal findings were managed with steroid eye drop treatment and dose modifications. Prophylactic eye drops were instituted early in the trial and appear to reduce the severity of corneal events in the weekly treatment schedule.

Ongoing trials
The SGN-CD19A phase I clinical trials are ongoing and additional data from both studies, including the impact of alternative dosing strategies, are planned in 2015. Seattle Genetics, the developer of the drug, plans to initiate a randomized phase II trial evaluating SGN-CD19A in combination with R-ICE chemotherapy for second-line DLBCL during 2015.