SBP-101, a polyamine metabolic inhibitor, administered in combination with gemcitabine and nab-paclitaxel, shows signals of efficacy as first-line treatment for subjects with metastatic pancreatic ductal adenocarcinoma.

Abstract

4127 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A fourth cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for phase 1b expansion. Interim Results: Fifty patients were enrolled (N=25, phase 1a and N=25, phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N= 6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring dose reduction or discontinuation. There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28 achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Median OS has not been reached. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation. Clinical trial information: NCT03412799.

The Polyamine Analogue Ivospemin Increases Chemotherapeutic Efficacy in Murine Ovarian Cancer

“…Through suppression of polyamine biosynthesis and upregulation of polyamine catabolism, ivospemin depletes essential polyamine pools from continuously growing cancer cells in vitro [ 19 ]. Additionally, ivospemin has been shown to be tolerable and potentially advantageous in a phase 1 clinical trial in pancreatic ductal adenocarcinoma [ 21 ]. Here, we evaluated the efficacy of the novel combination of ivospemin with a variety of chemotherapeutic agents used in platinum-refractory disease.…”

“…Previous studies have shown that ivospemin inhibits pancreatic and ovarian cancer both in vitro and in vivo [ 19 , 20 ]. Results from a multicenter phase 1a/b trial suggest that ivospemin is a tolerable and potentially advantageous addition to the standard of care (gemcitabine and nab-paclitaxel) in previously untreated metastatic pancreatic ductal adenocarcinoma (PDA) patients [ 21 , 22 ]. The combination of ivospemin and gemcitabine/nab-paclitaxel in metastatic PDA has progressed to the multi-center ASPIRE phase 2/3 clinical trial (NCT05254171) that is currently recruiting patients [ 23 ].…”

Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?

“…Preliminary results show partial responses in 12 of 28 assessable patients (43%) and 11 additional patients had stable disease at 8 weeks. 50 Another trial will evaluate SBP-101 in combination with gemcitabine and nab-paclitaxel versus chemotherapy alone in treatment-naive metastatic PDAC (NCT05254171).…”