California-based Sutro Biopharma has confirmed that the company will present preliminary results from the first 14 patients enrolled in the company’s ongoing Phase I study of STRO-001 (NCT03424603) at the upcoming European Hematology Association (EHA) Congress being held June 13-16, 2019, in Amsterdam, The Netherlands.[1]
The abstract of the poster presentation during EHA Congress summarizes the preliminary results of a clinical trial with the first CD74 targeting antibody-drug conjugate (ADC) called STRO-001 generated with Sutro’s novel cell-free protein synthesis technology, in patients with advanced B-cell malignancies.
CD74 is expressed on B cells throughout differentiation and is an attractive target for treatment of multiple myeloma and non-Hodgkin’s lymphoma.
STRO-001 is an ADC comprised of a human aglycosylated anti-CD74 IgG1 antibody (SP7219) genetically incorporating the non-natural amino acid para-azidomethy-L-phenyalanine (pAMF) to enable the site-specific conjugation of a non-cleavable dibenzocyclooctyne (DBCO)-maytansinoid linker-payload.
The investigational drug is developed using Sutro’s cell-free protein synthesis (XpressCF™) and site-specific conjugation (XpressCF+™) platform technologies.
Tolerability
This aim of the first-in-human Phase I, open-label, multicenter, dose escalation study was to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies.
The study enrolled patients with advanced, relapsed/refractory multiple myeloma and non-Hodgkin’s lymphoma. STRO-001 is administered as a 60-minute IV infusion on Days 1 and 15 of a 28-day cycle until disease progression or dose-limiting toxicity (DLT).
Two cohorts, one for patients with multiple myeloma and one for patients with non-Hodgkin’s lymphoma, with an initial accelerated dose titration design (N of 1) were enrolled and analyzed independently with 3+3 dose escalation being triggered by pre-specified safety events.
The 3+3 is the most commonly used rule-based dose escalation design which guides “up-and-down” decisions, using the modified Fibonacci mathematical series to determine the amount of dose increase for cohorts of sequentially enrolled patients.
The Fibonacci series ensures that dose increases are initially large but increments are smaller at higher dose levels
Preliminary Results
- A total of 14 patients (7 multiple myeloma and 7 non-Hodgkin’s lymphoma) were enrolled and treated at 7 dose levels: .05, .075, .15, .27, .43, .65 and .91 mg/kg.
- The non-Hodgkin’s lymphoma subtypes included: 2 follicular lymphoma (FL), 1 marginal zone lymphoma, 2 diffuse large B-cell lymphoma (DLBCL), 1 Burkitt’s lymphoma and 1 composite DLBCL/FL. 4 females and 10 males have been treated to date. Median age is 67 (r 21-82).
- Median ECOG performance – 1 (r 0-2). Median number of prior systemic therapies is 5 (range 2-12). Two patients (1-MM and 1-NHL) had received CAR-T therapy.
- Based on a related, grade 2 non-hematologic adverse event (fever, chills, vomiting), the 3+3 dose escalation design was triggered at the 0.91 mg/kg dose level in the NHL cohort.
- Median number of STRO-001 doses administered is 4 (r 1-12).
- 11 patients have completed at least one cycle (two doses) of STRO-001 and are evaluable for safety and for dose escalation recommendation.
- No grade ≥ 3 treatment-related adverse events (TRAEs) have been observed. The most common grade 1-2 TRAEs are fatigue, nausea, chills and infusion reaction occurring in 2 out of 11 patients.
- All treatment discontinuations have been secondary to disease progression.
- One patient with localized recurrence of DLBCL achieved a complete response (CR) after 2 cycles and progressed with new sites of disease after 12 doses (6 cycles).
- 3 patients remain on treatment and dose escalation is ongoing.
- Preliminary PK analysis showed maximum serum concentrations of ADC (0.39-8.2 µg/mL) and total antibody (0.41-9.1 µg/mL) increased after single IV doses of STRO-001 (0.05-0.65 mg/kg).
- The terminal phase half-life estimated for total antibody in 3 patients ranged 37-47 hours.
- STRO-001 did not exhibit evidence of accumulation with the 2 week dose interval. There is no evidence of anti-STRO-001 antibodies.
Conclusion
Based on the preliminary results, the researchers noted that STRO-001 has been well-tolerated, and the absence of immunogenicity is encouraging. They did not observe ocular toxicity or DLTs while MTD has not yet been reached.
The researchers observed preliminary anti-tumor activity (complete response) in a patient with recurrent Diffuse large B-cell lymphoma (DLBCL). The study continues to enroll patients in dose escalation with single patient multiple myeloma cohorts and 3+3 non-Hodgkin’s lymphoma cohorts.
STRO-001 was granted Orphan Drug Designation by the US Food and Drug Administration (FDA) for multiple myeloma in October 2018.
Reference
[1] Shah N, Krishnan A, Burke J, Melear J, Spira A, Popplewell L, Andreadis C, Chhabra S, Sharman J, et al. Preliminary results of a Phase I dose escalation studu of the first-in-class antibody-drug conjugate (ADC), STRO-001, In Patients with Advanced B-Cell Malignancies. EHA24 Learning Center. Matheny S. Saturday, June 15, 2019 from 17:30 – 19:00. Session topic: Aggressive Non-Hodgkin lymphoma Abstract (Poster Presentation): PS1071
[2] Study of STRO-001, an Anti-CD74 Antibody Drug Conjugate, in Patients With Advanced B-Cell Malignancies – NCT03424603
