December 4, 2020 - The first patient with higher-risk myelodysplastic syndrome has been dosed with a novel combination comprised of the next-generation CD47 blocker ALX148 plus azacitidine as part of the phase 1/2 ASPEN-02 study, the first of several planned studies to examine the agent in those with myeloid malignancies.
The first patient with higher-risk myelodysplastic syndrome (MDS) has been dosed with a novel combination comprised of the next-generation CD47 blocker ALX148 plus azacitidine as part of the phase 1/2 ASPEN-02 study (NCT04417517), the first of several planned studies to examine the agent in those with myeloid malignancies.1
Recently, the agent demonstrated promising safety and objective responses when used in combination with several agents, such as trastuzumab (Herceptin) and pembrolizumab (Keytruda), as well as with multiagent chemotherapy regimens in patients with gastric/gastroesophageal junction cancer (GEJ) and head and neck squamous cell carcinoma (HNSCC).
Preliminary findings from the ASPEN-01 trial (NCT03013218) presented during the 2020 SITC Annual Meeting,2 showed that after a median follow-up of 5.3 months, 14 patients with gastric/GEJ who received ALX148 in combination with trastuzumab, ramucirumab (Cyramza), and paclitaxel in the second-line setting experienced a median objective response rate (ORR) of 64.3% (95% CI, 38.8%-83.7%). Moreover, patients who received a 15 mg/kg dose of ALX148 had an ORR of 63.6% (95% CI, 35.4%-84.8%) after a median follow-up of 4.2 months. Patients who received the agent at a dose of 10 mg/kg achieved a slightly higher ORR of 66.7% (95% CI, 20.8%-93.9%) at a median follow-up of 8.9 months.
Additionally, a combination comprised of ALX148, pembrolizumab, 5-fluorouracil, and platinum-based chemotherapy elicited an ORR of 75% after a median of 5 months of follow-up (95% CI, 30.0%-95.0%) when used as a frontline treatment in 4 patients with HNSCC. After a median follow-up of 1.6 months, a 15 mg/kg dose of the agent resulted in an ORR of 100% in this patient population (95% CI, 20.5%-100%). Those who received the agent at a dose of 10 mg/kg achieved an ORR of 66.7% (95% CI, 20.8%-93.9%) after a median follow-up of 5.3 months.
Data from this trial, along with promising preclinical data from myeloid leukemia models, paved the way for ASPEN-02 and supported the FDA’s decision to grant fast track designations to ALX148 for use in the treatment of patients with gastric cancer and HNSCC.
“We are looking forward to evaluating the addition of ALX148 to azacitidine in patients with advanced MDS who are in need of effective new therapies,” Guillermo Garcia-Manero, MD, deputy chair of translational research, professor, and chief of the Section of Myelodysplastic Syndromes of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, stated in a press release. “ALX148 was designed for use in combination with a range of agents to maximize anti-cancer activity while minimizing associated toxicity.”
In the phase 1 portion of the ASPEN-02 study, investigators seek to determine the safety of ALX148 in combination with azacitidine in patients with relapsed/refractory or previous untreated higher-risk MDS. The second half of the study will be focused on evaluating the efficacy of the combination only in patients with previously untreated, higher-risk disease.
In the first portion of the study, patients will receive escalating doses of ALX148 along with azacitidine at an intravenous or subcutaneous dose of 75 mg/m2 for 7 days out of a 28-day cycle.3 In the second phase of the trial, treat patients will receive the recommended phase 2 dose of ALX148 in combination with the same dose and schedule of azacitidine evaluated in the phase 1 portion of the trial.
The primary end point of the phase 1 portion of the trial is focused on dose-limiting toxicities (DLT) up to 28 days measured by the number of participants with a DLT. In the phase 2 portion, the primary outcome measurement is ORR within 6 months measured by the number of participants who achieve a response per International Working Group criteria.
To be eligible for enrollment, patients must be 18 years of age or older and have acceptable renal and liver function, as well as an adequate performance status. For the first phase of the trial, patients must have a diagnosis of high-risk MDS that is either untreated or relapsed/refractory. In the phase 2 portion of the research, patients must have untreated higher-risk disease.
Patients who have previously undergone an allogeneic hematopoietic stem cell transplant for MDS or acute myeloid leukemia or who have received prior treatment with an anti-CD47, or anti-signal regulatory protein alpha agent cannot participate. Moreover, patients who have active viral infections such as hepatitis B and C, human immunodeficiency virus, acquired immunodeficiency syndrome, or the 2019 coronavirus disease, are also ineligible for inclusion.
“Through blockade of the CD47 myeloid checkpoint pathway, ALX148 bridges the innate and adaptive immune responses to cancer. This study builds upon the compelling combination activity observed in patients with ALX148 and multiple other anti-cancer agents,” Sophia Randolph, MD, PhD, chief medical officer at ALX Oncology, added in the release. “Our goal is to transform treatment options for patients with cancer by developing ALX148 as a foundational checkpoint immunotherapy.”