Date: 2015-12-06
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando, Florida, December 5-8, 2015
Company: Seattle Genetics (USA - WA)
Product: denintuzumab mafodotin (SGN-CD19A)
Action
mechanism: antibody drug conjugate. SGN-CD19A is an antibody drug conjugate (ADC) comprised of an anti-CD19 monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F (MMAF), using Seattle Genetics’ industry-leading proprietary technology. The ADC is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. CD19 is expressed in B-cell ALL and NHL, including DLBCL. 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. Preclinical data presented at the 2011 American Association for Cancer Research Annual Meeting demonstrated that SGN-CD19A effectively binds to target cells, internalizes and induces potent cell-killing activity and durable tumor regressions at low doses in multiple preclinical cancer models. SGN-CD19A is being evaluated in two ongoing phase 1 clinical trials for patients with B-cell ALL and aggressive NHL.
Disease: large B-cell lymphoma (DLBCL), B-lineage acute lymphocytic leukemia (B-ALL)
Therapeutic area: Cancer - Oncology - Rare diseases
Country:
Trial details:
Latest
news: * On December 6, 2015, Seattle Genetics highlighted clinical data with denintuzumab mafodotin (SGN-CD19A; 19A) in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphocytic leukemia (B-ALL), presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015. A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refractory B-Lineage Non-Hodgkin Lymphoma (Abstract #182, oral presentation on Sunday, December 6, 2015 at 7:45 a.m.): Data were reported from 62 patients with relapsed or refractory NHL, including 54 patients with DLBCL, five patients with mantle cell lymphoma and three patients with grade 3 follicular lymphoma. Of the 62 patients, 37 patients (60 percent) were refractory to their last therapy and 25 patients (40 percent) were relapsed. Sixteen patients (26 percent) 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 evaluate the safety and tolerability of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this study, patients receive 19A either every three weeks or every six weeks. Patients with stable disease or better are eligible to continue treatment with 19A. Key findings from an oral 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. The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received 19A in Schedule A (40 patients) at 0.3 to 3 mg/kg weekly or Schedule B (32 patients) at 4 to 6 mg/kg every three weeks. Key findings include: Of the 56 B-ALL adult patients evaluable for response, six patients (19 percent) treated weekly achieved a composite complete remission (complete remission or complete remission with incomplete platelet or blood recovery) and nine patients (38 percent) treated every three weeks achieved a composite complete remission. The median duration of response was 27 weeks. Fifty-four percent of patients across both schedules achieved cytoreduction of greater than 50 percent.
Of the 60 patients evaluable for response, 23 patients (38 percent) achieved an objective response, including 14 patients (23 percent) with a complete remission and nine patients (15 percent) with a partial remission. Thirteen patients (22 percent) achieved stable disease and 24 patients (40 percent) had disease progression.
Antitumor activity appeared to be higher in relapsed patients. Of the 25 relapsed patients, 15 patients (60 percent) achieved an objective response, including 10 patients (40 percent) with a complete remission. In the 23 relapsed patients who responded, median duration of response was 47.1 weeks. Among all relapsed patients, median progression-free survival was 25.1 weeks and median overall survival was 56.7 weeks.
The most common adverse events of any grade occurring in more than 15 percent of patients were blurred vision (63 percent); dry eye (53 percent); fatigue, keratopathy and photophobia (39 percent each). Ocular symptoms were reported in more than 70 percent of patients. Symptoms were mostly Grade 1/2 and were managed with steroid eye drop treatment and dose modifications. Eighty-eight percent of patients with Grade 3 or 4 keratopathy experienced improvement and/or resolution within a median of five weeks.
A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Adults with Relapsed or Refractory B-Lineage Acute Leukemia (B-ALL) and Highly Aggressive Lymphoma (Abstract #1328, poster presentation on Saturday, December 5, 2015): Data were reported from 72 adult patients with relapsed or refractory B-ALL and highly aggressive lymphomas, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 45 years and the median number of prior systemic therapies was two, with 20 patients (28 percent) having received a prior allogeneic stem cell transplant.
In the ten patients with Philadelphia chromosome positive (Ph+) B-ALL, five patients (50 percent) achieved a complete remission and one patient (10 percent) had a partial remission. Ph+ B-ALL represents 20 to 30 percent of adult patients and carries a dismal prognosis, with higher rates of relapse and lower overall survival.
The maximum tolerated dose was not reached in patients treated weekly and was identified at 5 mg/kg in patients treated every three weeks.
The most common adverse events of any grade occurring in 25 percent or more of patients treated weekly (40 patients) or every three weeks (32 patients), respectively, were nausea (63 and 41 percent), fatigue (58 and 47 percent), fever (55 and 50 percent), headache (45 and 38 percent) and anemia (43 and 22 percent).
In the study, 43 patients (60 percent) developed ocular symptoms, of which 91 percent were Grade 1/2. These included blurred vision (39 percent), dry eye (25 percent) and photophobia (19 percent). Ocular symptoms were managed with steroid eye drop treatment and dose modifications. Keratopathy was observed in 34 patients, of whom 22 patients had Grade 3/4 events. The majority of patients with Grade 3/4 events had improvement or resolution with a median time of approximately four weeks.
The 19A phase 1 clinical trials are ongoing. Separately, a randomized phase 2 trial has recently initiated evaluating 19A in combination with R-ICE chemotherapy for second-line DLBCL. In addition, a phase 2 clinical trial in frontline DLBCL is planned to begin in 2016.
