On June 3, 2018 Forty Seven, Inc., a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, reported proof-of-concept data from two separate clinical trials of 5F9: an ongoing Phase 1b/2 trial evaluating 5F9 in combination with rituximab in patients with relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL) and a Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) trial in patients with advanced solid tumors (Press release, Forty Seven, JUN 3, 2018, View Source [SID1234527178]). 5F9 is a monoclonal antibody against CD47, which is designed to block the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. The data are being presented in two oral presentations at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois, June 1-5, 2018.
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"We are pleased to present the first-in-human data for 5F9, which support our belief in the value of harnessing macrophages to fight difficult-to-treat cancers, and help validate our molecule selection strategy and the potential of our proprietary prime-maintenance dosing regimen to overcome the toxicity limitations of previously tested anti-CD47 antibodies," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of Forty Seven, Inc. "Together, the data presented at ASCO (Free ASCO Whitepaper) reveal an encouraging clinical profile for 5F9, suggesting that blocking CD47 can render difficult-to-treat tumors susceptible to phagocytosis. We are particularly encouraged by the evidence of anti-tumor activity observed in patients with r/r NHL and advanced, relapsed ovarian cancer, who are refractory to, or unfit for, existing therapeutic options. We are committed to exploring 5F9’s full potential and are now advancing a broad clinical development program at the recommended priming and Phase 2 dose and schedule, including multiple trials across a range of tumors and treatment modalities."
Data from the Phase 1b Portion of the Ongoing Phase 1b/2 Trial of 5F9 in Combination with Rituximab in r/r NHL
Forty Seven’s Phase 1b/2 trial is designed to evaluate 5F9 in combination with rituximab in patients with r/r NHL, including patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In the Phase 1b portion of the trial, patients received a 1 mg/kg priming dose of 5F9 to mitigate on-target anemia, followed by full doses of rituximab and escalating doses of 5F9, ranging from 10 mg/kg once weekly to 30 mg/kg once weekly. As of the data cutoff of April 2018, 22 patients had been treated across all dose groups in the Phase 1b portion of the trial, including 15 patients with DLBCL and seven patients with FL. Before dosing, 95% of patients were considered refractory to a prior rituximab regimen and the median number of prior therapies was four (ranging from two to 10).
Safety Data: As of the data cutoff date of April 2018, 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined with 5F9 dosing up to 30 mg/kg. The majority of adverse events (AEs) reported by investigators were Grade 1 or 2 and the most common treatment-related AEs were expected CD47-mechansim-based effects on red blood cells (RBC), which led to a temporary and reversible anemia. Other commonly reported AEs reported included chills, headache, infusion-related reaction and pyrexia. Only one patient discontinued due to an AE.
Clinical Data: As of the data cutoff date, 22 patients across all dose groups were evaluable for response assessment, including 15 patients with DLBCL and seven patients with FL. PET/CT imaging was used to measure clinical activity by the Lugano criteria, which include measures of tumor size and metabolic activity. Across all 22 evaluable patients, the data showed an objective response rate (ORR) of 50% and a complete response rate (CR) of 36%.
In DLBCL, the ORR was 40%, with 33% of patients achieving a CR.
In FL, the ORR was 71%, with 43% of patients achieving a CR.
Among all responding patients, only one patient has subsequently progressed with a median follow-up of over six months. A median duration of response has not been reached for either the DLBCL or FL patient populations, with a median follow-up of 6.2 months and 8.1 months for DLBCL and FL patients, respectively.
"Despite recent advancements, there remains a paucity of safe and effective therapies for patients with r/r NHL, especially for patients who are ineligible for transplantation or new cell therapies," said Sonali Smith, M.D., Elwood V. Jensen Professor in Medicine, an investigator for the study. "These preliminary data suggest that 5F9 may offer patients with DLBCL and FL a new treatment option that is both safe and easy to administer, and that can rapidly induce benefit, with a majority of responding patients showing clinical activity at first assessment with several complete remissions, despite being refractory to multiple prior regimens. I am excited to continue evaluating 5F9 in the Phase 2 portion of this trial, as we learn more about the clinical utility of this potentially transformative agent."
Data from the Phase 1 PK and PD Trial Evaluating 5F9 as a Single-Agent in Advanced Solid Tumors
Forty Seven’s Phase 1 trial was designed to evaluate the safety and tolerability of 5F9 and to define a recommended dose and schedule. A total of 62 patients were treated in the Phase 1 trial. This included 11 patients treated in Part A at four escalating priming doses (ranging from 0.1 mg/kg to 3 mg/kg once weekly); 14 patients treated in Part B at a priming dose of 1 mg/kg and three escalating maintenance doses (ranging from 3 mg/kg to 20 mg/kg once weekly); 15 patients treated in a tumor biopsy cohort at a priming dose of 1 mg/kg and a maintenance dose of 20 mg/kg; and 22 patients treated in Part C at a priming dose of 1 mg/kg and three escalating loading and maintenance doses (ranging from 20 mg/kg to 45 mg/kg once weekly). The treated patients had advanced tumors including colorectal, ovarian, salivary, breast and other solid tumors and were heavily pre-treated, with a median of five prior systemic treatments.
PK and PD: In Part A, 1 mg/kg was identified as the optimal priming dose sufficient to saturate CD47 on RBCs and trigger a compensatory reticulocytosis to mitigate the expected anemia due to the removal of older RBCs. PK data showed that 5F9 can overcome the CD47 antigen sink at doses of 10 mg/kg or higher, with free plasma drug levels exceeding the expected therapeutic range based on preclinical results. PK data at saturating dose levels also showed a mean half-life of approximately 13 days, supporting a maintenance dose once every two weeks. The Recommended Phase 2 Dose (RP2D) has been defined as a 1 mg/kg priming dose, followed by 30 mg/kg once weekly for three weeks, followed by a maintenance dose of 30 mg/kg every two weeks.
Safety Data: 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined up to 45 mg/kg. The majority of AEs reported by investigators were Grade 1 or 2. The most common treatment-related AEs were expected CD47-mechanism-based effects on RBC, including a predictable and frequently transient anemia that was successfully mitigated by Forty Seven’s priming and maintenance dosing regimen. Other frequently reported treatment-related AEs included infusion-site reactions, headache, fatigue, chills, fever and nausea, which were generally mild-to-moderate in severity and easily managed.
Clinical Data: Preliminary evidence of anti-tumor activity with single-agent 5F9 was observed in the study:
In ovarian cancer, two patients had a confirmed partial response (PR) by RECIST 1.1 criteria. Both patients were treated at weekly maintenance doses of 20 mg/kg and were heavily pre-treated, having failed at least six previous treatment regimens. One of these patients had a durable PR of more than six months.
"I am particularly encouraged by the single-agent activity of 5F9 in patients with advanced, relapsed ovarian cancer, especially for women with platinum-resistant tumors who are less responsive to other therapies," said Amita Patnaik, M.D., FRCPC, Co-Director of Clinical Research at South Texas Accelerated Research Therapeutics and an investigator for this study. "These early clinical responses for 5F9 as a single agent, coupled with strong preclinical data, support Forty Seven’s combination strategy in ovarian cancer, including the recently initiated Phase 1b trial combining 5F9 with the anti-PD-L1 inhibitor, avelumab, under the Company’s existing collaboration with Merck KGaA."
About 5F9:
5F9 is a monoclonal antibody against CD47 that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. Forty Seven, Inc. is initially developing 5F9, an investigational medicine, for the treatment of patients with solid tumors, acute myeloid leukemia, non-Hodgkin’s lymphoma and colorectal cancer. 5F9 has been granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma, two forms of B-cell non-Hodgkin’s lymphoma.